PCAF regulates cardiac muscle function via non-epigenetic regulation of ACTA1 acetylation

Historically, lysine acetylation has been studied in the epigenetic regulation of gene expression, in which it is known to play key roles in cardiac remodeling and dysfunction. However, recent evidence suggests that non-histone protein acetylation of myofilament proteins is also important for the regulation of cardiac contractility and relaxation. Lysine acetyltransferase (KAT) enzymes serve as writer proteins to acetylate histone and non-histone proteins. PCAF (p300/CBP associated factor) belongs to the GNAT family of lysine acetyltransferases and has been implicated in left ventricular hypertrophy (LVH), in which pharmacological inhibition of PCAF attenuated stress-induced LVH that was linked to changes in gene expression. Consistent with these reports, we show that garcinol, a p300/PCAF inhibitor, attenuated 2-weeks of isoproterenol-induced LVH, cardiac output (CO) and stroke volume (SV) in C57BL6J mice. Of interest, isoproterenol increased skeletal muscle alpha actin (ACTA1) protein acetylation in the left ventricle (LV) of mice and this was attenuated by garcinol treatment. ACTA1 is a fetal gene that is re-expressed in the myocardium of diseased hearts. These data imply that KATs acetylate (i.e. post-translational modification) this re-expressed gene, yet how acetylation of ACTA1 impacts cardiac function remains unclear. To determine this, we performed tail-vein injections of an adeno-associated virus (AAV) expressing either LacZ or an ACTA1 acetyl-mimic and performed echocardiography and gross morphology measurements in C57BL6J mice two-weeks post injection. Here, we report that pseudo-acetylation of ACTA1 increased LVH, and reduced fractional shortening (FS) and ejection fraction (EF) in mice. Lastly, we show that PCAF acetylated ACTA1 but not cardiac myosin; p300 failed to acetylate ACTA1 in vitro. Combined, these data suggest that PCAF acetylates ACTA1 to regulate cardiac contractility in response to β-adrenergic over-activation. While PCAF can serve as an epigenetic regulator of gene expression, these data highlight a non-epigenetic role for PCAF in cardiac function. Funding: This research was funded by the USDA NIFA (Hatch-NEV00767), the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research, the National Institute for General Medical Sciences (NIGMS) of the NIH (P20 GM130459), the National Heart, Lung, and Blood Institute of the NIH (R15 HL143496), National Institute of Aging of the NIH (R21 AG077248) and NSF EPSCOR Track II (OIA-1826801) to B.S.F. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.