title: Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.
abstract: Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) 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 RARαKO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RARαKO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RARαKO mouse hearts, which were rescued by overexpression of RARα in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) was observed in RARαKO mouse hearts. Ca2+reuptake and cardiomyocyte relaxation were delayed by RARα deletion. Overexpression of RARα or inhibition of ROS generation or NOX activation prevented RARα deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+reuptake. Moreover, the gene and protein expression of RARα was significantly decreased in aged or metabolic stressed mouse hearts. RARα 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 RARα 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 RARαKO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARα signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction.
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: Sen
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States; Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States. Electronic address: rsguleria@medicine.tamhsc.edu.
authors.forename: Rakeshwar S
authors.initials: RS
authors.lastname: Guleria
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: Candice M
authors.initials: CM
authors.lastname: Thomas
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Roth
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: Fnu
authors.initials: F
authors.lastname: Gerilechaogetu
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States; Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States; Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Baker
authors.affiliation: Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States; Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Central Texas Veterans Health Care System, Baylor Scott & White Health, Temple, TX, United States. Electronic address: jpan@medicine.tamhsc.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003971:Diastole; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005355:Fibrosis; D017353:Gene Deletion; D015870:Gene Expression; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D000072482:Retinoic Acid Receptor alpha / Q000172:deficiency*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D000072482:Retinoic Acid Receptor alpha; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Calcium handling; Diastolic dysfunction; Oxidative stress; Retinoic acid receptor