Oleanolic acid attenuates cardiac hypertrophy by improving endothelial mitochondrial function and inhibiting pyroptosis

Abstract

Purpose: Cardiac microvascular impairment serves a function in cardiac hypertrophy (CH). Oleanolic acid (OA), a bioactive pentacyclic triterpenoid substance, has been extensively investigated for its anti-inflammatory and antioxidant characteristics. This investigation sought to elucidate the involvement of pyroptosis and mitochondrial malfunction in microvascular damage and examine the potential of OA in inhibiting pyroptosis and mitigating endothelial injury.

Methods: We utilized a rat CH model and performed several experiments, encompassing network pharmacology, molecular docking, western blot, morphological analysis, mitochondrial membrane potential detection, mitochondrial oxygen consumption rate assay and enzyme-linked immunosorbent assay kit detection.

Results: Network pharmacology approaches were employed to forecast the potential molecular targets of OA. The results showed that OA interacts with signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-B (NF-κB), peroxisome proliferator-activated receptor gamma (PPARG), and Interleukin-1β (IL-1β). Echocardiography data showed that OA remarkably improves cardiac function, and inhibits CH in rats. Mechanistically, upregulation of p-STAT3 expression, NF-κB p65 and IL-1β, but downregulation of PPARG could be detected in the hearts of CH rat and in cardiac microvascular endothelial cells (CMECs) exposed to Ang II. In addition, OA decreased STAT3 and NF-κB phosphorylation and up-regulated PPARG, thereby inhibiting pyroptosis and improving mitochondrial function.

Conclusion: OA rescued mitochondrial function and inhibited CMEC pyroptosis by directly interacting with PPARG, STAT3, NF-κB, and IL-1β, and then suppressed CH.

Keywords: cardiac hypertrophy; cardiac microvascular endothelial cells; mitochondrial function; oleanolic acid; pyroptosis.