Oroxylin A prevents cardiac hypertrophy and dysfunction as a modulator of mitochondrial protein acetylation

Abstract

Cardiac hypertrophy and remodeling are both well‐known consequences mediated by increased levels of Angiotensin II (Ang II) as a compensatory mechanism in non‐ischemic HF. In this sense, mitochondrial protein hyper‐acetylation and ROS production that induce mitochondrial dysfunction have previously been associated with this condition. Oroxylin A (OA) is a methylated flavone found on the root of Scutellaria baicalensis known for its antioxidant properties, and as a modulator of mitochondrial deacetylase activity. Nevertheless, OA effects have not been explored in cardiac remodeling mediated by exacerbated ROS production and mitochondrial hyper‐acetylation. Therefore, we explore the potential cardioprotective effect of OA in an in vitro model of cardiac hypertrophy induced by Ang II treatment in H9c2 myocytes. We found that OA reverted completely the Ang II mediated hypertrophic and cell death effect. Mitochondrial acetylation profile and sirtuin3 expression analyzed by western blot showed that Ang II promotes ~2‐fold increase in protein acetylation; however, OA pre‐treatment abrogates Ang II‐induced hyper‐acetylation in a dose‐dependent fashion. Remarkably, we found that the OA pre‐treatment prevents mitochondrial dysfunction by decreasing significantly permeability transition susceptibility and membrane potential depolarization. These results were consistent with a decrease in apoptosis, determined by caspase 9 and 3,7 activity. Overall, these findings suggest that OA promotes sirtuin3 activation, targeting pivot mitochondrial proteins. Accordingly, we evaluated the cardioprotective effect of OA in an in vivo model of HF induced by AngII+L‐NAME. In this model, we found an increased mitochondrial acetylation in the myocardium and found that OA was capable of prevent cardiac hypertrophy and dysfunction. Taken together, our results suggest that OA is a novel strategy to treat cardiac dysfunction in HF.Support or Funding InformationThis work was partially supported by Xignus Research Foundation as well endowed Chair in Cardiology/Grupo de Enfoque Medicina Cardiovascular Tec de Monterrey, CONACYT Grant CB‐256577, Fronteras de la Ciencias 0682 (Gerardo García‐Rivas), and Red Temática Farmoquímicos del CONACYT.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.