Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.
Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.
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心肌视黄酸受体α的丧失通过促进成年小鼠的细胞内氧化应激和钙不当而诱导舒张功能障碍。
DOI：
10.1016/j.yjmcc.2016.08.009
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发表时间：
2016-10
影响因子：
5
通讯作者：
Pan, Jing
中科院分区：
文献类型：
--
作者：
Zhu, Sen;Guleria, Rakeshwar S.;Thomas, Candice M.;Roth, Amanda;Gerilechaogetu, Fnu;Kumar, Rajesh;Dostal, David E.;Baker, Kenneth M.;Pan, Jing
视黄酸受体（RAR）参与了病理性刺激诱导的心脏重构。为了确定RARα信号的损伤是否直接参与心功能障碍的发生及其机制，我们采用他莫昔芬诱导心肌特异性RARα缺失（RARα ko）小鼠。超声心动图和心导管检查显示基因缺失16周后出现明显的舒张功能障碍。然而，RARαKO与野生型（WT）对照小鼠的左室射血分数（LVEF）无显著差异。DHE染色显示RARαKO小鼠心脏细胞内活性氧（ROS）生成增加。RARα - ko小鼠心肌细胞过表达RARα后，心肌细胞中NOX2 （NADPH氧化酶2）和NOX4水平显著升高，SOD1和SOD2水平显著降低。在RARαKO小鼠心脏中观察到SERCA2a表达和磷酸化磷酸化（PLB）降低，Akt和Ca2+/钙调素依赖性蛋白激酶II δ (CaMKII δ)磷酸化降低。RARα缺失延迟了Ca2+再摄取和心肌细胞舒张。过表达RARα或抑制ROS生成或NOX激活可阻止RARα缺失引起的SERCA2a表达/激活降低和延迟Ca2+再摄取。衰老或代谢应激小鼠心脏RARα基因及蛋白表达显著降低。RARα缺失加速链脲佐菌素（STZ）诱导的1型糖尿病小鼠或高脂饮食小鼠舒张功能障碍的发展。结论：心肌RARα缺失促进舒张功能障碍，LVEF相对保留。氧化应激增加在rar α - ko小鼠SERCA2a和Ca2+处理不当的表达/激活降低中起重要作用，这是舒张功能障碍发生的主要因素。这些数据表明，心脏RARα信号的损害可能是一种与病理性刺激诱导的舒张功能障碍直接相关的新机制。
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 16 wks 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.
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影响因子：
4.4
作者：
Jia, Weitao;Shaffer, Justin F.;Harris, Samantha P.;Leary, Julie A.
通讯作者：
Leary, Julie A.
DOI：
10.1152/ajpheart.01301.2007
发表时间：
2008-02-01
影响因子：
4.8
作者：
Choudhary, Rashmi;Palm-Leis, Ants;Pan, Jing
通讯作者：
Pan, Jing
影响因子：
20.1
作者：
Hamdani, Nazha;Krysiak, Judith;Linke, Wolfgang A.
通讯作者：
Linke, Wolfgang A.
影响因子：
5
作者：
Fraysse B;Weinberger F;Bardswell SC;Cuello F;Vignier N;Geertz B;Starbatty J;Krämer E;Coirault C;Eschenhagen T;Kentish JC;Avkiran M;Carrier L
通讯作者：
Carrier L
影响因子：
20.1
作者：
Ide, T;Tsutsui, H;Takeshita, A
通讯作者：
Takeshita, A