Pharmacological Inhibition of the Cysteine Protease Cathepsin C Improves Graft Function after Heart Transplantation in Rats

Background: Heart transplantation (HTX) is the standard treatment for end-stage heart failure. Nevertheless, reperfusion following an ischemic period can contribute to myocardial injury. Neutrophil infiltration, along with the subsequent release of tissue-degrading neutrophil elastase (NE)-related serine proteases and oxygen-derived radicals, is associated with adverse graft outcomes. Inhibition of cathepsin C (CatC) has been demonstrated to block NE-related protease activation. We hypothesized that the CatC inhibitor BI-9740 improves graft function after HTX.

Methods: The recipient Lewis rats received either a placebo (n = 12) or BI-9740 (n = 11, 20 mg/kg body weight) once daily for 12 days. Donor hearts from untreated rats were explanted, preserved in cold cardioplegic solution for 1 hour, and subsequently heterotopically implanted. In vivo left-ventricular (LV) graft function was assessed after 1 hour of reperfusion. The proteolytic activity of neutrophil serine proteases was determined in bone marrow lysates from rats treated with BI-9740- and placebo. Additionally, myocardial morphological changes were examined, and heart samples underwent immunohistochemistry.

Results: The NE-related proteolytic activity in bone marrow cell lysates was markedly decreased in the BI-9740-treated rats compared to those receiving the placebo. Histopathological lesions, elevated CatC and myeloperoxidase-positive cell infiltration, and nitrotyrosine immunoreactivity with an increased number of poly(ADP-ribose) polymerase (PARP)-1-positive cells were lowered in the BI-9740-hearts when compared to placebo group. Within the implanted graft, improvements were observed in both systolic function (LV systolic pressure 110 ± 6 vs. 74 ± 6 mmHg; maximum rate of rise of LV pressure dP/dtmax 2782 ± 149 vs. 2076 ± 167 mmHg/s, LV developed pressure 105 ± 6 vs. 71 ± 6 mmHg, at an intraventricular volume of 200 µl, p < 0.05) and diastolic function (maximum rate of fall of LV pressure dP/dtmin 2096 ± 252 vs. 1505 ± 143 mmHg/s, at an intraventricular volume of 170 µl, p < 0.05) in the BI-9740-hearts compared with those receiving the placebo. Additionally, BI-9740 was associated with a significantly shorter graft re-beating time compared to the placebo group.

Conclusion: We provided experimental evidence that pharmacological inhibition of CatC improves graft function after HTX in rats.

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2024