NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy

TLDR

Dilated cardiomyopathy is a leading cause of heart failure, yet its underlying mechanisms remain largely unknown. This study aimed to determine whether NLRP3 inflammasome‑mediated pyroptosis drives non‑ischemic dilated cardiomyopathy and to elucidate the involved pathways. In doxorubicin‑treated hearts, up‑regulation of NOX1/NOX4 and Drp1‑mediated mitochondrial fission activates the NLRP3 inflammasome and caspase‑1‑dependent pyroptosis, while inhibition of NOX1/NOX4 or Drp1 blocks this cascade. Hyperactivated NLRP3 inflammasome and cardiomyocyte pyroptosis were observed in DCM patient myocardium and in doxorubicin‑induced models, correlating with impaired cardiac function and being absent in NLRP3‑ or caspase‑1‑deficient mice, demonstrating a causal role for pyroptosis in DCM progression.

Abstract

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, and the underlying mechanism remains largely elusive. Here we investigated whether NLRP3 inflammasome-mediated pyroptosis contributes to non-ischemic DCM and dissected the underlying mechanism. We found that hyper activated NLRP3 inflammasome with pyroptotic cell death of cardiomyocytes were presented in the myocardial tissues of DCM patients, which were negatively correlated with cardiac function. Doxorubicin (Dox)-induced DCM characterization disclosed that NLRP3 inflammasome activation and pyroptosis occurred in Dox-treated heart tissues, but were very marginal in either NLRP3-/- or caspase-1-/- mice. Mechanistically, Dox enhanced expressions of NOX1 and NOX4 and induced mitochondrial fission through dynamin-related protein 1 (Drp1) activation, leading to NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes via caspase-1-dependent manner. Conversely, both inhibitions of NOX1 and NOX4 and Drp1 suppressed Dox-induced NLPR3 inflammasome activation and pyroptosis. The alterations of NOX1 and NOX4 expression, Drp1 phosphorylation and mitochondrial fission were validated in DCM patients and mice. Importantly, Dox-induced Drp1-mediated mitochondrial fission and the consequent NLRP3 inflammasome activation and pyroptosis were reversed by NOX1 and NOX4 inhibition in mice. This study demonstrates for the first time that cardiomyocyte pyroptosis triggered by NLRP3 inflammasome activation via caspase-1 causally contributes to myocardial dysfunction progression and DCM pathogenesis.