Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice

Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RAR alpha signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARa deletion (RAR alpha KO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16 wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RAR alpha KO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RAR alpha KO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RAR alpha KO mouse hearts, which were rescued by overexpression of RARa in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II delta (CaMKII delta) was observed in RAR alpha KO mouse hearts. Ca2+ reuptake and cardiomyocyte relaxation were delayed by RARa deletion. Overexpression of RARa or inhibition of ROS generation or NOX activation prevented RAR alpha deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+ reuptake. Moreover, the gene and protein expression of RARa was significantly decreased in aged or metabolic stressed mouse hearts. RARa deletion accelerated the development of diastolic dysfunction in streptozotocin (STZ)-induced type 1 diabetic mice or in high fat diet fed mice. In conclusion, myocardial RARa deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca2+ mishandling in RAR alpha KO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARa signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction. (C) 2016 Elsevier Ltd. All rights reserved.