Andrographolide and its Derivatives in Cardiovascular Disease: A Comprehensive Review

Abstract

Cardiovascular disease is one of the main causes of mortality worldwide. Andrographolide represents an important category of natural phytochemicals that has significant therapeutic potential in various conditions such as acute lung injury, heart disease, and viral infections due to its anti-oxidative, anti-inflammatory, and anti-apoptotic properties. This compound plays a protective role in human pathophysiology. This review provides a comprehensive overview of the effects of andrographolide on cardiovascular disease and examines its essential roles and mechanisms in cardiovascular disease and other vascular dysfunctions. The data collected in this review serve as a comprehensive reference for the role of andrographolide in cardiovascular disease and provide valuable insights for further research and the development of andrographolide as a novel therapeutic approach for cardiovascular disease.

Keywords

andrographolide - cardiovascular disease - heart

Introduction

Cardiovascular disease has emerged as a major global health problem that has contributed significantly to mortality and disability in recent decades. In the World Health Organizationʼs (WHO) “World Health Statistics 2022′′, cardiovascular diseases are classified as highly fatal diseases, underlining their far-reaching impact on public health. Despite the severity of the problem, there has been a remarkable and encouraging 27% decrease in global mortality from cardiovascular disease between 2000 and 2019 [1]. This decline represents a positive trend in the treatment and understanding of cardiovascular disease and indicates progress in prevention, diagnosis, and treatment. The decline in mortality underscores the global efforts and innovations in achieving various treatment options to combat this complex and multifaceted health problem. In the current landscape of cardiovascular research, increasing emphasis is being placed on exploring the potential of natural products, both in their natural form and in the form of synthetic derivatives, as a source of preventative and therapeutic formulations. Researchers and medical practitioners are increasingly turning to natural compounds, often derived from plants or other biological sources, to investigate their efficacy and safety in the treatment of cardiovascular disease. The interest in natural products stems from their diverse pharmacological properties, which include anti-inflammatory, antioxidant, and vasodilatory effects. These properties make natural products an interesting approach for the development of interventions that could complement or improve existing strategies for the prevention or treatment of cardiovascular disease. The ongoing exploration of natural products in cardiovascular research reflects the general trend to adopt holistic and integrative approaches to address the multi-factorial nature of cardiovascular disease and improve patient outcomes.

Andrographolide (AGP), a bioactive diterpene lactone extracted from the traditional medicinal plant Andrographis paniculata, has attracted attention for its pharmacological effects, although it has a robust first-pass effect. In previous studies, administration of AGP at dosages of 5 mg/kg or 30 mg/kg has shown efficacy in attenuating lipopolysaccharide (LPS)-induced osteoporosis, highlighting its potential therapeutic applications beyond traditional uses [2]. Another intriguing compound, double andrographolide C, identified from Andrographis paniculata, exhibits a unique ability to activate transient receptor potential V1 (TRPV1) and transient receptor potential V3 (TRPV3) channels. This activation serves as a protective mechanism that protects myocardial cells from hypoxia-reoxygenation injury, which may be important in the context of myocardial ischemia and related diseases [3].

In addition, the versatility of AGP and its derivatives also extends to the area of anti-tumor, antiviral, and anti-inflammatory activities. These positive effects are primarily attributed to its antioxidant and anti-angiogenic properties, which underlines the compoundʼs potential for a wide range of therapeutic applications [4]. Of particular interest in the context of cardiovascular health are several studies demonstrating the protective effects of AGP and its derivatives against cardiovascular disease, including myocardial ischemia and myocardial hypertrophy [5], [6], [7]. These findings suggest that AGP is a promising therapeutic agent for cardiovascular diseases, and they pave the way for further exploration of its mechanisms and applications in the treatment of cardiovascular diseases. This review summarizes recent advances in our understanding of AGP and its derivatives and highlights their potential role in the treatment of cardiovascular disease.

Cardiovascular Disease: Incidence, Pathophysiology, and Risk Factors

Cardiovascular disease (CVD) is a pressing health problem, especially in people over the age of 60, and contributes significantly to global morbidity and mortality. In 2016, 17.9 million people died from cardiovascular disease, which corresponds to around 31% of the global death rate. Most notably, heart disease and stroke together accounted for 85% of these deaths, highlighting the severity of these diseases [8]. As a result, the number of deaths attributable to cardiovascular disease increased from 12.3 million (25.8% of total deaths) in 1990 [9]. Over the years, the pattern of the burden of cardiovascular disease has shifted remarkably. In developing countries, the mortality rate has increased since the 1970 s, while it has decreased in industrialized countries [10], [11]. Worrying projections suggest that the number of annual deaths from cardiovascular disease could rise to 23.3 million by 2030 [12]. CVD can be primarily classified into two major categories based on their etiopathogenesis: i) atherosclerosis-related CVD, which constitutes the predominant pathological mechanism–this category encompasses three principal manifestations: ischemic heart disease, also termed coronary artery disease (CAD), cerebrovascular disorders, and aortic and arterial diseases (including both hypertensive vascular pathology and peripheral vascular disease); ii) non-atherosclerotic cardiovascular conditions, comprising congenital cardiac anomalies, rheumatic heart disease, primary cardiomyopathies, and cardiac rhythm abnormalities [13].

Numerous high-risk factors contribute significantly to the development and progression of cardiovascular disease. Smoking, diabetes, hypertension, and hypercholesterolemia are among the most influential risk factors. Importantly, these risk factors are largely controllable, emphasizing the potential for timely intervention measures to reduce the burden of cardiovascular disease [14]. Smoking, for instance, is associated with oxidation and inflammation of arterial walls and creates a favorable environment for serious complications such as vascular rupture and occlusion. Diabetes, hypertension, and hypercholesterolemia also contribute to the pathological processes that lead to cardiovascular disease. This emphasizes the importance of targeted interventions to address these modifiable risk factors [15]. Understanding and managing these risk factors plays a critical role in preventing and mitigating the effects of cardiovascular disease on a global scale.

Structure, Origin, and Bioavailability of AGP

AGP is a natural diterpene compound that is present in the form of white, rectangular, or lamellar crystals with the molecular formula C₂₀H₃₀O₅. This compound is extracted from the stems and leaves of Andrographis paniculata, a medicinal plant [16]. Its chemical structure consists of a benzene ring and a terpene structure. Below this, the terpene structure contains a carboxylic acid ester group ([Fig. 1]). The biological activities of AGP are extensive and diverse and include anti-inflammatory [17], anti-cancer, anti-viral [18], and hepatoprotective functions. The versatility of AGP has made it a subject of great interest in various areas of medical research.

Fig. 1 2D (Ⅰ) and 3D (Ⅱ) Structures of Andrographolide.

The oral bioavailability of AGP was reported to be only 2.67% [19]. In terms of pharmacokinetics, Rammohan Bera et al. conducted studies in rats to determine the key parameters for AGP. The results showed an apparent maximum concentration (C_max) of 115.81 ng/ml after 0.75 hours, an elimination half-life of 2.45 hours, and a total exposure (AUC _0-α ) of 278.44 ngh/ml. These parameters provide valuable insights into the absorption, distribution, metabolism, and excretion of AGP in the rat model [20].

Tissue distribution studies have provided information on the preferential accumulation of AGP in different organs. Kidney tissue showed the highest concentration of AGP, indicating a significant presence in the kidneys. This was closely followed by liver, spleen, and brain, which also showed significant concentrations of AGP. Interestingly, the concentrations in the heart and lungs were almost identical. This distribution profile suggests a possible role for AGP in these vital organs and warrants further investigation of its specific effects and mechanisms of action in tissues, particularly those involved in cardiovascular and respiratory functions [20]. A comprehensive understanding of the pharmacokinetics and tissue distribution of AGP forms the basis for exploring its therapeutic potential in various medical applications.

Several factors influence the bioavailability of AGP, which can be categorized as follows. i) Solubility: AGP has a reported solubility of only 3.29 ± 0.73 µg/ml in water at 25 °C [21], resulting in limited solubility in the gastrointestinal tract and consequently limiting absorption. ii) Intestinal permeability: due to its molecular weight of 350.45 g/mol and its high lipophilicity, AGP has difficulty crossing the water-soluble gastrointestinal mucosal layer, resulting in poor oral absorption. In vitro permeability experiments using the Caco-2 cell monolayer model revealed a low apparent permeability coefficient for AGP, suggesting limited transport across intestinal epithelial cells and poor intestinal permeability [22]. iii) P-glycoprotein (P-gp)-mediated exocytosis: P-gp, a transmembrane protein in intestinal epithelial cells, pumps certain drugs from the cells into the intestinal lumen. AGP can be a substrate for P-gp, leading to its extrusion during intestinal absorption and further reducing oral bioavailability [23]. iv) First-pass metabolism: this phenomenon is the initial metabolism of an orally administered drug in the liver after gastrointestinal absorption, mainly by the cytochrome P450 (CYP450) enzyme system, reducing the concentration of the active drug entering the systemic circulation. Studies suggest that AGP is predominantly metabolized by the CYP450 enzyme system in the liver, thereby reducing the concentration of the active drug [24].

The low solubility of AGP poses a number of challenges to exploiting its medicinal value. i) Limited absorption: the low solubility of AGP leads to limited absorption in the gastrointestinal tract, as only the dissolved fraction is available for absorption. Consequently, the poor solubility leads to insufficient drug concentrations in the blood. ii) Variable bioavailability: the bioavailability of AGP can vary greatly from person to person due to its poor solubility. Physiological factors such as gastric pH, gastrointestinal motility, and the presence of food can influence this variability, making it difficult to predict therapeutic outcomes. iii) Formulation challenges: the development of effective AGP formulations is hampered by its poor solubility. Conventional formulations, such as tablets or capsules, may not achieve sufficient solubility or absorption, so advanced delivery systems are required. iv) Enhanced metabolism and efflux: the low solubility also makes AGP more susceptible to enzymatic degradation and efflux by transporters such as P-gp before it reaches the systemic circulation. This complexity further complicates efforts to improve bioavailability.

To address the challenges of low bioavailability and poor solubility of AGP, researchers have made considerable efforts. For instance, Xu et al. developed a solid self-dispersing drug delivery system (Andro-SNDS) using nanocrystals and direct compression technology that contained nanocrystalline AGP particles. This novel system exhibited a solubility of 85.87% in water after 30 minutes and was administered to rats via gavage at a dose of 10 mg/kg. The resulting C_max (299.32 ± 78.54 ng/mL) and AUC_0-∞ (4440.55 ± 764.13 mg/L·h) were significantly higher than those of AGP alone (77.52 ± 31.73 ng/mL and 1437.79 ± 354.25 mg/L·h), which markedly increased the oral bioavailability of AGP [25]. Similarly, Ma et al. prepared a solid dispersion based on AGP nanocrystals (AG-NC-SD) by a combination of homogenization and spray drying. Pharmacokinetic analysis revealed that the C_max and AUC_0-∞ for crude AGP were 52.506 ± 10.652 µg/L and 379.521 ± 124.233 µg/L·h, respectively, when administered to rats at a dose of 20 mg/kg by gavage. In contrast, AG-NC-SD achieved C_max and AUC_0-∞ values of 346.741 ± 38.163 µg/L and 1794.738 ± 311.213 µg/L·h, respectively, significantly improving the oral bioavailability of AGP [26].

Researchers have innovatively combined AGP with β-cyclodextrin to form an andrographolide-β-cyclodextrin inclusion complex (AG-β-CD). Unlike penicillin, which is only effective when administered via the lungs, both AGP and AG-β-CD can inhibit bacterial growth and reduce inflammation by modulating the immune response. In addition, the anti-inflammatory effect of AG-β-CD is significantly greater than that of AGP, which is due to the improved solubility of AGP in the lung facilitated by β-cyclodextrin [27].

Chemical Structures, Pharmacokinetics, Therapeutic Effects, and Safety Profiles of AGP Derivatives

This review focuses on the cardiovascular effects of AGP and its derivatives. Therefore, it is important to summarize their chemical structures, pharmacokinetics, therapeutic efficacy, and safety profiles. ([Fig. 2]) provides an overview of these aspects for various AGP derivatives. Although these derivatives are not classified as chemically or physically hazardous based on the available safety data sheets, comprehensive studies on their toxicological properties are lacking.

Fig. 2 Summary of chemical structures, pharmacokinetics and therapeutic effects of AGP derivatives.

Cardiovascular Effects of AGP: Pharmacological Effects and Potential Therapeutic Targets

AGP and its derivatives have significant medicinal value as pharmacologically active diterpene compounds. Numerous in vitro and in vivo studies describe their beneficial properties. This article provides a comprehensive review of the advances in research on the therapeutic potential and mechanisms of action of AGP and its derivatives in the cardiovascular system.

Effects of AGP on atherosclerosis and coronary heart disease

Atherosclerosis, recognized as a chronic inflammatory disorder, initiates with the deposition of modified lipoproteins in the subendothelial matrix through binding to proteoglycans [43], [44]. Subsequent pathological progression involves the accumulation of low-density lipoprotein (LDL) and cholesterol within arterial walls. Oxidative modification of LDL (oxLDL) via macrophage internalization facilitates lipid overload, which is internalized through scavenger receptor-A (SR-A), culminating in foam cell formation. The aggregation of foam cells generates fatty streaks and atheromatous plaques [45], ultimately provoking vascular stenosis, structural destabilization, and thrombotic complications that may result in partial or complete arterial occlusion [46].

Hypercholesterolemia constitutes a well-established risk factor for both CVD and atherosclerosis [47]. Murine models fed a high-fat/cholesterol/bile acid diet (HFCCD) exhibit dysregulated lipid metabolism, cellular injury, and hypercholesterolemia [48]. Mechanistic investigations by Chen et al. revealed that HFCCD-fed mice displayed marked aortic lipid deposition accompanied by upregulated expression of intercellular adhesion molecule-1 (ICAM-1) and interleukin-1β (IL-1β). Notably, AGP supplementation attenuated lipid accumulation and significantly suppressed IL-1β levels, with concomitant reductions in ICAM-1 expression. These findings align with prior studies demonstrating that downregulation of ICAM-1 and IL-1β in apolipoprotein E-deficient (ApoE-/-) mice ameliorates atherosclerotic lesions [49], [50]. In vitro analyses further revealed that AGP reduced oxLDL-induced lipid accumulation in bone-marrow-derived macrophages by modulating NLRP3 inflammasome activation (upregulating NLRP3, Caspase-1, and IL-1β) while suppressing SR-A-mediated oxLDL uptake [51]. Histopathological evaluations confirmed AGPʼs efficacy in attenuating aortic lipid deposition and intimal hyperplasia in rabbits, with morphometric analyses demonstrating reduced plaque burden at aortic roots of ApoE-/- mice [52], [53].

To address AGPʼs poor aqueous solubility, Wu et al. engineered ROS-responsive polymeric micelles using PEG-PPS diblock copolymers for testosterone co-delivery. These micelles undergo hydrophilic transition upon ROS exposure at pathological sites, enabling targeted drug release. Given the pivotal roles of inflammation and oxidative stress in atherogenesis, in vitro experiments demonstrated that PEG-PPS/AGP micelles (45 µg/mL, containing 3.5 µg/mL AGP) significantly inhibited LPS-induced IL-6 and MCP-1 expression in macrophages, reduced phospho-p65 levels, and attenuated oxidative stress. In vivo validation confirmed enhanced therapeutic efficacy, highlighting this platformʼs potential for atherosclerosis management [54].

Endothelial dysfunction, a hallmark of CAD, exhibits strong inflammatory coupling [55]. AGP administration (10 – 50 mg/kg) improved high-fat diet (HFD)-induced endothelial dysfunction in mice by elevating nitric oxide (NO) and prostacyclin-I2 (PGI-2) while reducing thromboxane A2 (TxA2) and endothelin-1. AGP also enhanced fibrinolysis via increased tissue plasminogen activator (t-PA) and decreased plasminogen activator inhibitor-1 (PAI-1). Macrophage polarization shifted toward an anti-inflammatory phenotype (reduced CD86/CD206 ratio) with concomitant decreases in tumor necrosis factor-α (TNF-α), MCP-1, hypersensitive C-reactive protein (hs-CRP), and IL-1β. Mechanistically, AGP attenuated myocardial injury by enhancing Caspase-3 expression and peroxisome proliferator-activated receptor alpha (PPARα) activity while inhibiting NF-κB signaling (p65 and IκB-α) [56].

In clinical practice, coronary artery bypass grafting remains a mainstay for CAD treatment. However, saphenous vein grafts exhibit high occlusion rates (up to 50% within 10 years) due to neointimal hyperplasia and secondary atherosclerosis [57], [58]. Preoperative AGP administration (200 mg/kg/day for 2 days) in rat venous graft models significantly reduced intimal hyperplasia at 2 – 8 weeks post-surgery. Transcriptional analyses revealed AGP-mediated suppression of p65, E-selectin, and matrix metalloproteinase-9, providing mechanistic insights into its anti-proliferative effects [59].

Despite promising preclinical evidence, AGP research faces three major limitations: (1) predominant reliance on in vitro and animal models without robust clinical validation; (2) suboptimal pharmacokinetic profiles due to poor solubility, despite advances in nanodelivery systems; (3) lack of long-term safety and efficacy data. Future investigations should prioritize multicenter clinical trials to establish AGPʼs therapeutic index in humans; systems-level elucidation of AGPʼs anti-inflammatory and antioxidant mechanisms; combinatorial strategies with statins or PCSK9 inhibitors for synergistic effects; development of next-generation delivery platforms to enhance bioavailability.

Effects of AGP and its derivatives in hypertension and myocardial hypertrophy

Heart failure (HF) represents a complex multisystem syndrome arising from dysregulated compensatory mechanisms, ultimately impairing cardiac output and systemic perfusion [60]. Pathological myocardial hypertrophy, a critical precursor to HF progression, develops through heterogeneous etiologies including hypertension, dilated cardiomyopathy, genetic predisposition, and myocarditis. While current research on AGPʼs antihypertensive effects remains limited, preliminary investigations suggest therapeutic promise. Mali et al. engineered an inhalable dry powder formulation combining AGP with carrier polysaccharides, demonstrating enhanced pulmonary deposition efficiency coupled with blood pressure reduction in preclinical models [61]. Complementary findings by Yoopan et al. revealed that the AGP derivative 14-deoxy-11,12-didehydroandrographolide induces vasodilation and significantly lowers blood pressure in rodent hypertension models [62].

Mechanistic studies employing transverse aortic constriction mouse models demonstrated AGPʼs capacity to attenuate pathological hypertrophy through downregulation of B-type natriuretic peptide (BNP) and angiotensin II (Ang II) levels [63]. In vitro analyses further elucidated that AGP suppresses Ang II-induced hypertrophy in H9c2 cardiomyocytes via inhibition of endoplasmic reticulum stress pathways.

Notably, Heish et al. identified that AGP counteracts HFCCD-induced myocardial hypertrophy and apoptosis through potentiation of insulin-like growth factor 1 receptor (IGF-1R) signaling, providing novel insights into its cardioprotective mechanisms [64]. Collectively, these findings position AGP and its derivatives as multifunctional agents targeting maladaptive cardiac remodeling in HF pathogenesis.

Despite encouraging preclinical data, three key limitations necessitate resolution. i) Mechanistic ambiguity: the precise molecular targets and signaling cascades mediating AGPʼs cardiovascular effects remain incompletely characterized. Advanced techniques (CRISPR screening, proteomics, and metabolomics) could systematically map AGPʼs interactome. ii) Pathophysiological complexity: current studies predominantly focus on isolated pathways, overlooking HFʼs multifactorial nature. Future work should evaluate AGPʼs efficacy across heterogeneous etiologies (genetic, metabolic, immune-mediated). iii) Translational barriers: The pharmacokinetic profile and tissue-specific bioavailability of AGP derivatives require optimization for clinical applicability.

AGP-based interventions demonstrate pleiotropic effects against myocardial hypertrophy through modulation of neurohormonal activation, cellular stress responses, and growth factor signaling. While substantial preclinical validation supports their therapeutic potential, concerted efforts to address mechanistic and translational challenges will be essential for clinical development.

Protective effects of AGP and its derivatives in myocardial infarction and ischemic stroke

Myocardial infarction (MI), a severe cardiovascular disorder, induces detrimental consequences including cardiomyocyte apoptosis, cardiac dysfunction, and structural remodeling [65]. In an experimental study by Elasoru, rats were divided into four groups: control, isoproterenol (ISO)-treated, AGP-treated, and AGP+ISO co-treated groups. The control group received saline for 21 days, while the ISO group was administered saline for 19 days followed by ISO (80 mg/kg/day) on days 20 – 21. The AGP group received daily AGP (20 mg/kg) throughout the 21-day period, and the AGP+ISO group was co-administered AGP with ISO during the final two days. The results demonstrated that AGP pretreatment significantly attenuated ISO-induced myocardial infarction through multiple mechanisms: inhibition of L-type calcium channels, enhancement of transient outward potassium current, augmentation of antioxidant capacity, reduction in infarct size, and suppression of myocardial injury biomarkers [66].

Nevertheless, several limitations warrant consideration in interpreting these findings. While the ISO model remains widely utilized for acute cardiac injury research, its pathological relevance to human MI requires cautious interpretation. The ISO-induced injury primarily stems from sympathetic nervous system overstimulation rather than replicating clinically relevant mechanisms such as vascular occlusion or ischemia-reperfusion injury, potentially limiting its clinical extrapolation. Furthermore, although AGP exhibited promising antioxidant properties, critical questions persist regarding its sustained efficacy during prolonged or repeated administration, particularly in elderly populations or patients with comorbidities. To advance this research, four key directions merit attention: First, future studies should prioritize the use of more clinically relevant animal models such as coronary artery ligation models to better recapitulate the complex pathophysiology of human MI. Second, while AGPʼs cardioprotective effects involve ion channel modulation and oxidative stress mitigation, detailed molecular mechanisms require elucidation through advanced molecular biology techniques. Third, rigorous preclinical investigations and randomized controlled trials must validate AGPʼs therapeutic potential in clinical settings, particularly focusing on dosage optimization, administration routes, and long-term safety profiles. Finally, considering the heterogeneous nature of MI patient populations, personalized treatment strategies should be explored to maximize therapeutic efficacy across diverse demographic and clinical subgroups.

Benefits of AGP for valvular heart disease

Calcific aortic valve disease (CAVD), a prevalent cardiac valvulopathy characterized by aortic leaflet thickening, fibrosis, and mineralization [67], represents a significant global health burden. Epidemiological data from the WHO indicate that over 20% of individuals aged above 60 years are affected by CAVD, with substantial implications for both quality of life and healthcare expenditures [68], [69]. The pathological progression of CAVD leads to valvular stenosis, reduced cardiac output, and subsequent complications including coronary hypoperfusion, angina pectoris, and heart failure [70]. While surgical intervention remains the primary therapeutic approach for advanced cases [71], a critical gap persists in developing effective pharmacological interventions for early stage valvular pathology [72]. Valvular interstitial cells (VICs) have been identified as central mediators in CAVD pathogenesis, where inflammatory stimuli trigger their proliferative activation and osteogenic differentiation. This process is marked by upregulated expression of calcification-related biomarkers including bone morphogenetic protein-2 and runt-related transcription factor 2 (Runx2), ultimately culminating in calcium deposition [73]. Huang et al. demonstrated that 10 µM AGP administration effectively suppressed osteogenic transformation and cellular proliferation in VICs through modulation of MAPK-ERK1/2 and NF-κB signaling pathways. In vivo validation using ApoE-/- mice fed a HFCCD for 24 weeks revealed that oral administration of 10 mg/kg AGP significantly attenuated valvular thickening and downregulated Runx2 expression, confirming its anti-calcification effects via coordinated regulation of MAPK-ERK1/2 and NF-κB/Akt cascades [74], [75]. However, these findings present notable limitations: the restricted dosage range examined and the exclusive focus on a single cell type diminish their translational relevance, while the long-term efficacy and safety profile of AGP across diverse pathological contexts remain inadequately characterized due to insufficient preclinical longitudinal studies.

Contrasting metabolic investigations by Wang et al. employing GC-MS metabolomics identified significant upregulation of unsaturated fatty acid synthesis and triglyceride metabolism in VICs from CAVD patients. Subsequent experimental validation established that AGP-mediated inhibition of monoacylglycerol lipase and alkaline phosphatase expression effectively curtails lipid metabolic dysregulation and reduces aortic valve calcification [76]. Under pathological conditions, cellular metabolism undergoes a characteristic shift from oxidative phosphorylation to aerobic glycolysis [77]. Multi-omics analyses further revealed AGPʼs regulatory role in glycolytic pathways, with mechanistic studies demonstrating its capacity to reduce lactate accumulation. Through suppression of p300 enzymatic activity and consequent inhibition of H3K9la lactylation, AGP attenuates Runx2-mediated osteogenic differentiation in VICs [78], [79]. Nevertheless, current research inadequately addresses the dynamic interplay between lipid metabolic reprogramming and CAVD progression, particularly regarding stage-specific alterations in metabolic pathways. Elucidation of these temporal metabolic changes could unveil novel therapeutic targets for pharmacological development.

The emerging evidence positions AGP as a promising candidate for CAVD mitigation, though critical challenges persist in translating these findings into clinical applications. Comprehensive assessment of both acute therapeutic effects and long-term prognostic outcomes remains imperative for establishing AGPʼs clinical viability. Future investigations should prioritize the development of stage-specific intervention strategies targeting early valvular lesions, complemented by systematic longitudinal studies to evaluate AGPʼs sustained impact on CAVD progression. Concurrent exploration of AGPʼs pleiotropic effects on intersecting metabolic and signaling pathways may yield synergistic therapeutic approaches, potentially revolutionizing current management paradigms for this prevalent cardiovascular disorder.

Benefits of AGP and its derivatives for myocardial ischemia-reperfusion injury

Myocardial infarction (MI) represents a critical cardiovascular condition where current therapeutic strategies, including early thrombolysis and percutaneous coronary intervention, primarily aim to improve prognosis by reducing infarct size [80]. However, these interventions may paradoxically induce myocardial ischemia-reperfusion injury (MIRI), characterized by secondary myocardial damage following blood flow restoration, which triggers cellular apoptosis. This dual challenge of addressing both infarction management and reperfusion injury mitigation constitutes a significant scientific priority. Woo et al. investigated the cardioprotective effects of andrographolide (AGP) and its derivatives (14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide) on neonatal rat cardiomyocytes (NRCs) under hypoxic conditions [81]. Their findings revealed that 10 µM AGP significantly enhanced antioxidant enzyme activities and glutathione (GSH) levels, while the derivatives showed negligible effects. Notably, AGP pretreatment exhibited time-dependent protection, with 12-hour pretreatment initiating significant cytoprotection that progressively intensified until 33 hours. Subsequent investigations demonstrated that AGP-mediated protection against hypoxia-reoxygenation injury in NRCs operates through GSH elevation, an effect reversible by γ-glutamylcysteine synthetase inhibition [82].

Further mechanistic insights by Xie et al. identified AGPʼs dual role in enhancing post-MI antioxidant capacity while attenuating cardiac remodeling through suppression of fibrogenic proteins (transforming growth factor-beta and phosphorylated SMAD family member 3) and activation of the Nrf2/HO-1 signaling pathway [83]. Expanding the pharmacological potential, Gao et al. developed a novel AGP derivative, bisandrographolide, which demonstrated protective effects against hypoxia-reoxygenation injury through selective activation of TRPV1 – 4 channels [84]. Although in vivo evidence of AGPʼs efficacy against MIRI remains pending, compelling data from cerebral ischemia-reperfusion models show AGP modulates neuroprotective pathways (glial fibrillary acidic protein, neuronal nuclei protein, and tropomyosin receptor kinase B) and suppresses pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) via PI3K/Akt signaling [85]. These collective findings position AGP and its structural analogs as promising candidates for MIRI intervention, warranting comprehensive preclinical evaluation to elucidate their therapeutic potential in cardiovascular pathologies.

Benefits of AGP in diabetic cardiomyopathy

The increasing prevalence of diabetes has been paralleled by a rising incidence of diabetic cardiomyopathy (DCM), a pathological condition characterized by cardiac dysfunction, myocardial hypertrophy, and cardiomyocyte apoptosis. Liang et al. conducted a study investigating the potential therapeutic effects of AGP in a murine DCM model [86]. Utilizing 8-week-old C57/BL6J mice, diabetes was induced through intraperitoneal administration of streptozotocin (STZ, 50 mg/kg) for five consecutive days [87]. Subsequent oral administration of AGP at doses of 1, 10, and 20 mg/kg/day for 12 weeks demonstrated dose-dependent cardioprotective effects, with control groups receiving either 20 mg/kg/day AGP alone or normal saline. Diabetic mice exhibited significant myocardial dysfunction accompanied by inflammatory activation, elevated oxidative stress, hypertrophic remodeling, and fibrotic changes [88], [89]. The study demonstrated that AGP administration (10 and 20 mg/kg/day) significantly improved cardiac function by inhibiting hyperglycemia-induced ROS generation. Mechanistically, AGP exerts its cardioprotective effects through anti-inflammatory and antioxidant mechanisms, including suppression of NADPH oxidase activation and subsequent ROS production. Furthermore, AGP enhanced cellular antioxidant capacity via Nrf2 pathway upregulation, thereby mitigating DCM-associated myocardial damage.

Despite these promising findings, several limitations warrant consideration. The STZ-induced diabetes model fails to fully recapitulate the complex metabolic dysregulation and cardiovascular comorbidities observed in human diabetic patients, potentially limiting the clinical translatability of these results. While the study provides preliminary evidence of AGPʼs antioxidant properties through ROS reduction and Nrf2 activation, the precise molecular mechanisms underlying these effects remain incompletely characterized. The selected dose range (1 – 20 mg/kg/day) established basic efficacy parameters but lacked comprehensive pharmacokinetic-pharmacodynamic correlation analysis, particularly regarding long-term cardiovascular safety profiles and optimal therapeutic dosing. Although AGPʼs multimodal action targeting inflammation and oxidative stress presents therapeutic advantages, the current data lack systematic evaluation of its systemic impacts. Critical questions persist regarding potential off-target effects on hepatic and renal systems, as well as the compoundʼs tissue-specific bioavailability and metabolic fate. Future investigations should prioritize mechanistic studies to delineate AGPʼs molecular targets, coupled with comprehensive toxicological assessments to establish its safety profile across multiple organ systems. Additionally, translational research employing clinically relevant models that better mimic human diabetic pathophysiology would strengthen the rationale for clinical trials.

Benefits of AGP and its derivatives for other cardiovascular diseases

Atrial fibrillation (AF), the most prevalent clinical arrhythmia, significantly compromises cardiac function and increases thromboembolic risk, contributing substantially to cardiovascular mortality [90], [91]. Current therapeutic strategies encompassing pharmacological interventions (antiarrhythmic and anticoagulant agents) [92] and invasive procedures (e.g., catheter ablation) [91] demonstrate limited efficacy, with only partial patient responsiveness [93], [94], [95]. In an innovative approach, Yu et al. established an AF model through 6-hour rapid atrial pacing (RAP) in rabbits, categorizing subjects into sham-operated, RAP, RAP+AGP (10 mg/kg intraperitoneal AGP administration 24 hours pre-RAP), and AGP-only groups [96]. Complementary in vitro investigations using HL-1 cardiomyocytes involved sham control, rapid electrical stimulation (RES: 5 Hz, 10 V, 24 h), and RES+AGP (25 µmol/L post-RES treatment) groups. Notably, AGP administration mitigated RAP/RES-induced electrophysiological remodeling, inflammatory activation, oxidative damage, and apoptosis through enhanced mitochondrial bioenergetics mediated by Nrf2 nuclear translocation and heme oxygenase-1 (HO-1) upregulation, suggesting novel therapeutic potential for AF management [97]. However, this study did not systematically evaluate dose-response relationships or temporal therapeutic windows, as the singular 10 mg/kg dose precluded comprehensive pharmacokinetic analysis. Future investigations should establish optimized dosing regimens while assessing potential tachyphylaxis and long-term safety profiles of chronic AGP administration.

Thromboembolism remains a principal contributor to cerebrovascular mortality. While aspirin maintains widespread clinical utilization for thromboprophylaxis, Yin et al. demonstrated superior antithrombotic efficacy of dehydroandrographolide succinate (DAS) through enhanced coagulation regulation and platelet aggregation inhibition [98]. Nevertheless, the molecular mechanisms underlying DASʼs anticoagulant properties remain poorly characterized. Current evidence derived solely from in vitro assays and rodent models necessitates validation through human clinical trials. Subsequent research should elucidate DASʼs multifaceted interactions with vascular endothelium, platelet membrane receptors, and coagulation cascades while establishing its therapeutic index in translational models.

In oncological therapeutics, chemotherapeutic agents including doxorubicin (DOX) and arsenic trioxide (ATO) exhibit dose-limiting cardiotoxicity. Mechanistic studies reveal ATO-induced cardiomyocyte apoptosis through ROS overproduction, antioxidant enzyme suppression, endoplasmic reticulum stress activation, and calcium homeostasis disruption [99], [100]. Similarly, DOX cardiotoxicity manifests via ROS generation, phosphocreatine depletion, TLR2/4-NF-κB pathway activation, and subsequent inflammatory cascades [101], [102], [103], [104]. Safaeian et al. investigated AGPʼs cardioprotective potential (0.5 – 10 µM) against chemotherapy-induced cytotoxicity in H9c2 cardiomyocytes. Pretreatment with 2.5 – 10 µM AGP significantly attenuated DOX/ATO-induced toxicity through TLR4 downregulation and enhanced antioxidant capacity, suggesting therapeutic adjunct potential [105]. However, limitations including restricted sample sizes and absence of chronic exposure data underscore the need for comprehensive safety evaluations in clinically relevant models. Future studies must prioritize longitudinal assessments of AGPʼs cardioprotective efficacy while establishing pharmacokinetic-pharmacodynamic correlations in coexisting oncological and cardiovascular pathologies.

Clinical Studies on AGP and its Derivatives

As the medical value of AGP becomes increasingly clear, the number of corresponding clinical studies are growing. However, a search of PubMed (https://pubmed.ncbi.nlm.nih.gov/) and ClinicalTrials.gov (https://clinicaltrials.gov/) reveals that no clinical trials have specifically investigated the effects of AGP on the cardiovascular system. In particular, Kan Jang, a fixed combination of extracts of Andrographis paniculata (Burm. F.) Wall. ex Nees and Eleutherococcus senticosus (Rupr. & Maxim.) Maxim, has been studied for its therapeutic effect on coronavirus disease 2019 (COVID-19). In a randomized, quadruple-blind, placebo-controlled, double-parallel group study by Ratiani et al. [106], 140 patients received either 6 Kan Jang capsules (n = 68, containing 90 mg AGP) or a placebo (n = 72) together with supportive therapy (paracetamol) for 14 days. The results showed that Kan Jang significantly reduced the rate of severe cases (17.86%), reduced the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during treatment, and reduced the absolute risk of severe cases by 12.5%. In addition, patients in the Kan Jang group had a shorter recovery time and a greater reduction in inflammatory symptoms, including cough, sore throat, rhinitis, and muscle pain. Kan Jang also improved physical activity and exercise, but had no effect on cognitive function, quality of life, or inflammatory markers such as D-dimer and C-reactive protein compared to the placebo group. These results suggest that AGP may have promising therapeutic effects, and future clinical trials should investigate its potential benefits in cardiovascular disease.

Advantages and Disadvantages: AGP and Conventional Treatment of Cardiovascular Disease

Conventional treatments for cardiovascular disease typically include medications (such as antihypertensives, antiplatelets, and statins), lifestyle interventions (including dietary change, weight control, and smoking and alcohol cessation), and surgical and interventional therapies. Compared to these conventional treatments, AGP offers both benefits and limitations. AGP exhibits significant anti-inflammatory and antioxidant effects that may attenuate inflammation and oxidative stress in the cardiovascular system, presenting potential therapeutic value for the prevention and treatment of atherosclerosis, myocardial ischemia, and other cardiovascular disease. In addition, AGP targets multiple molecular signaling pathways, such as inhibition of the NF-κB pathway and modulation of inflammatory factor expression, which may be beneficial for integrated management of the complex pathological processes in cardiovascular disease. Some studies suggest that AGP has relatively low toxicity and fewer adverse effects compared with certain conventional drugs, which may make it safer for long-term use [107]. However, several limitations need to be considered. (i) Insufficient clinical evidence: despite promising results in animal models and in vitro studies, there is a lack of large-scale clinical trials demonstrating the efficacy of AGP in cardiovascular disease. (ii) Pharmacokinetic properties: the low bioavailability and rapid metabolism of AGP in vivo may limit its clinical application, highlighting the need to improve its bioavailability and stability. (iii) Lack of comparative studies: most research focuses on AGP alone, with few direct comparisons with conventional treatments. (iv) Individual differences: the efficacy of AGP may vary due to individual differences in metabolism, absorption, and immune response, underscoring the need for individualized approaches in clinical use.

Conclusion

AGP exhibits significant anti-inflammatory and antioxidant properties and exerts therapeutic effects on cardiovascular diseases by targeting factors such as NLRP3, MAPK, ERK1/2, GSH, and Nrf2 ([Fig. 3]). However, research on AGP and its derivatives in cardiovascular diseases is relatively limited. There are few reports on critical diseases such as myocardial ischemia-reperfusion injury and valvular heart disease. Although AGP and its derivatives show promise for the treatment of cardiovascular disease, their high first-pass elimination rate is a significant obstacle to realizing their therapeutic potential. Researchers have explored the combination of AGP with various carrier materials to enhance its efficacy, and further combinations with other materials promise to maximize its effectiveness in the treatment of cardiovascular disease. This offers a wealth of opportunities for the comprehensive evaluation and utilization of these fascinating phytochemicals.

Fig. 3 Cardiovascular actions and molecular targets of Andrographolide by figdraw.com [rerif].

Research Methodology

The key words “andrographolide”, “cardiovascular disease”, and “heart” were searched in Google Scholar and PubMed, covering the period from 1995 to 2024. The authors reviewed the relevant articles and selected appropriate content for summarization.

Contributorsʼ Statement

Draft: Shenjie Zhang, Xiaokai Xie, Juan Zhao, Yilong Jiang, Qi Li, Boyu Xia; Review & Edit: Chao Huang, Le Yin, Xiaomei Yuan, Qingsheng You

Conflict of Interest

The authors declare that they have no conflict of interest.

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