Targeting HSP90 suppresses STAT1/CCL8-driven inflammation and mitigates mitochondrial dysfunction to attenuate hypertension-induced atrial fibrillation.

Abstract

BACKGROUND: The pathogenesis of atrial fibrillation (AF) is believed to be a synergistic interaction of multiple signaling pathways. As an essential molecular chaperone, HSP90 has pleiotropic effects in cardiovascular diseases. However, its underlying mechanisms in hypertension-induced AF remain unclear. This study sought to determine whether HSP90 acts as a master regulator that directly orchestrates mitochondrial dysfunction and inflammation to facilitate AF progression. METHODS AND RESULTS: We employed bioinformatic analysis, an in vivo AF mouse model induced by AngII infusion, and in vitro experiments using HL-1 atrial cardiomyocytes. After target identification using RNA sequencing, we examined the effects of the specific HSP90 inhibitor 17AAG on AF inducibility, atrial electrophysiology, fibrosis, mitochondrial function, and inflammation. Mechanistically, we found that HSP90 activated DRP1 (Dynamin-related protein 1, Ser616) through promoting ERK phosphorylation to induce excessive mitochondrial fission and reactive oxygen species production along a first pathway. In contrast, HSP90 interacted with transcription factor STAT1 and stabilized its expression to drive the expression of the chemokine CCL8 and recruit macrophages and mediate local atrial inflammation along a second pathway. STAT1 knockdown attenuated CCL8 upregulation and the inflammatory cascade. CONCLUSION: We demonstrated that HSP90 acts as a key driver for AF during hypertension. It facilitates the formation of an arrhythmogenic atrial substrate by directly promoting the ERK/DRP1-mediated mitochondrial fission and STAT1/CCL8 driven inflammation. However, inhibition of HSP90 simultaneously attenuates both pathological remodeling processes. Thus, HSP90 inhibition represents a promising pleiotropic therapy for AF, providing a novel conceptual and mechanistic basis for AF prevention and treatment.