The Regenerative Capacity of the Right Ventricle Reveals a Novel Therapeutic Approach for Left Ventricular Myocardial Fibrosis

Background: Myocardial fibrosis remains a major clinical burden with limited therapeutic options. In contrast to the left ventricle (LV), the right ventricle (RV) has a substantial ability to regenerate after myocardial injury. In this project we aimed to identify the differences in regenerative mechanisms between RV and LV and to deduce a potential therapeutic strategy to counteract myocardial fibrosis.

Methods: Myocardial fibrosis was induced in a murine ischemic and temporary HFpEF model in both ventricles. Myocardial infarction was induced via ligation of either the left anterior descending or the right coronary artery. Afterload was increased by banding either the aorta or the pulmonary artery with an absorbable suture. RNA sequencing was performed for both ventricles separately to identify differentially expressed genes during regeneration. Ventricular functions were evaluated weekly via transthoracic echocardiography. Myocardial fibrosis was analyzed in histological sections. Functional fibrosis assays, such as BrdU and scratch assays, and animal experiments were performed with cells or mice lacking identified antifibrotic genes. In a therapeutic approach, overexpression of antifibrotic genes was induced in mice. Overexpressing adeno-associated virus (AAV) was injected intramyocardially upon induction of LV myocardial infarction; heart function and fibrosis were assessed thereafter.

Results: RV function recovered after myocardial infarction or temporarily increased afterload in contrast to the LV. In parallel, a decrease in fibrotic scar tissue was observed in the RV. RNA sequencing revealed upregulation of specific antifibrotic gene signatures in the RV during regeneration. Functional in vitro assays confirmed anti-fibrotic effects of the identified genes. Increased proliferation rates and increased cell migration were observed in fibroblasts lacking the identified genes. In mice lacking the discovered gene signature, no regeneration of the RV was observed with increased scar size. Intramyocardial injection of an adeno-associated virus overexpressing the antifibrotic genes after LAD ligation resulted in improved LV function and decreased scar size.

Conclusion: The RV shows improved regenerative capacity myocardial infarction and temporarily increased afterload. We discovered an undescribed anti-fibrotic gene in the regenerative RV. Applied in LV as an anti-fibrotic therapy, the gene represents a promising novel therapeutic approach to counteract myocardial fibrosis.

Publikationsverlauf

Artikel online veröffentlicht:
11. Februar 2025