Histone Deacetylase 6 Controls Atrial Fibrosis and Remodeling in Postinfarction Mice Through the Modulation of Wnt3a/GSK-3β Signaling.

Myocardial infarction (MI)-induced hemodynamic disorder often causes atrial structural and electrophysiological remodeling. Given that histone deacetylase 6 (HDAC6) plays important roles in pathobiology, we investigated the molecular mechanism underlying MI-induced atrial remodeling in mice, with a special focus on HDAC6-mediated Wnt3a/GSK3β signaling activation. We observed an upregulation of HDAC6 expression in the left atria of mice at 2 weeks post-MI, accompanied by atrial enlargement, increased atrial fibrosis and inflammation, myocyte hypertrophy, impaired mitochondrial biogenesis, elevated levels of Wnt3a, GSK3β, and β-catenin protein, and reduced gap junction CX43 expression; these alterations were reversed by HDAC6 deletion. This atrialoprotective effect was mimicked by HDAC6 inhibition with the HDAC6 inhibitor tubastatin A (TubA). In HL1 mouse atrial myocytes, HDAC6 silencing (or overexpression) reduced (increased) the Wnt3a and p-GSK3β protein levels, providing evidence and a mechanistic explanation of HDAC6-mediated Wnt3a/GSK3β signaling activation in mitochondrial oxidative stress production and cell pyroptosis. After HDAC6 formed a complex with GSK3β and translocated into the mitochondria, GSK3β competitively bound with TFAM to mtDNA, thereby affecting mitochondrial function and ROS generation. The SGLT2 inhibitor dapagliflozin exhibited efficacy that was comparable to that of TubA by inhibiting HDAC6 signaling in mice. These results indicate an essential role of HDAC6 in atrial remodeling in response to post-MI stress, possibly via the modulation of Wnt3a/GSK3β-mediated mitochondrial oxidative stress production and pyroptosis and matrix protein production, and they suggest a novel therapeutic strategy for the prevention of post-MI-related atrial morphological and electrophysiological remodeling by regulating HDAC6 activity.