Inhibition of 15-PGDH by SW033291 ameliorates age-related heart failure in mice

Abstract

Chronic loss of cardiomyocyte integrity underlies human heart failure associated with aging that often involves progression of acute myocardial infarction and the maladaptive response of cardiomyopathy. SW033291, an inhibitor of 15-prostaglandin dehydrogenase (15-PGDH), has been shown to mitigate fibrosis of mice heart. Whether it has cardioprotective effect remain unknown. Young and aged C57BL/6 J mice were treated with either the vehicle or SW033291 for four weeks. The expression of the target gene was assessed by RT-qPCR, Western blotting, and ELISA. Cardiac function was measured by echocardiography. Our study demonstrated that SW033291 induced a notable upregulation of prostaglandin E2 while concurrently downregulated the expression of both 15-PGDH and troponin I in cardiac tissues, encompassing both young and aged mice. Notably, the administration of SW033291 resulted in a significant improvement in systolic and diastolic function among aged mice, although this effect was not observed in their younger counterparts. Subsequent investigations focusing on exploring the mechanisms, revealed that repetitive administration of SW033291 effectively mitigated age-induced oxidative stress and curtailed chronic inflammation within the cardiac tissues of aged mice. These pivotal findings establish a solid foundation for contemplating the prospective therapeutic application of SW033291 in addressing age-related heart failure.