| First Author | Zhu S | Year | 2016 |
| Journal | J Mol Cell Cardiol | Volume | 99 |
| Pages | 100-112 | PubMed ID | 27539860 |
| Mgi Jnum | J:250835 | Mgi Id | MGI:6101628 |
| Doi | 10.1016/j.yjmcc.2016.08.009 | Citation | Zhu S, et al. (2016) Loss of myocardial retinoic acid receptor alpha induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice. J Mol Cell Cardiol 99:100-112 |
| abstractText | Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARalpha signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARalpha deletion (RARalphaKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RARalphaKO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RARalphaKO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RARalphaKO mouse hearts, which were rescued by overexpression of RARalpha in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKII delta) was observed in RARalphaKO mouse hearts. Ca(2+) reuptake and cardiomyocyte relaxation were delayed by RARalpha deletion. Overexpression of RARalpha or inhibition of ROS generation or NOX activation prevented RARalpha deletion-induced decrease in SERCA2a expression/activation and delayed Ca(2+) reuptake. Moreover, the gene and protein expression of RARalpha was significantly decreased in aged or metabolic stressed mouse hearts. RARalpha 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 RARalpha deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca(2+) mishandling in RARalphaKO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARalpha signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction. |
