Nakagawa Hitoshi, Oberwinkler Heike, Nikolaev Viacheslav O, Gaßner Birgit, Umbenhauer Sandra, Wagner Helga, Saito Yoshihiko, Baba Hideo A, Frantz Stefan, Kuhn Michaela
From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
Circ Heart Fail. 2014 Sep;7(5):814-21. doi: 10.1161/CIRCHEARTFAILURE.113.000885. Epub 2014 Jul 15.
The endocrine balance between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone system is critical for the maintenance of arterial blood pressure and volume homeostasis. This study investigated whether a cardiac imbalance between ANP and aldosterone, toward increased mineralocorticoid receptor (MR) signaling, contributes to adverse left ventricular remodeling in response to pressure overload.
We used the MR-selective antagonist eplerenone to test the role of MRs in mediating pressure overload-induced dilatative cardiomyopathy of mice with abolished local, cardiac ANP activity. In response to 21 days of transverse aortic constriction, mice with cardiomyocyte-restricted inactivation (knockout) of the ANP receptor (guanylyl cyclase [GC]-A) or the downstream cGMP-dependent protein kinase I developed enhanced left ventricular hypertrophy and fibrosis together with contractile dysfunction. Treatment with eplerenone (100 mg/kg/d) attenuated left ventricular hypertrophy and fully prevented fibrosis, dilatation, and failure. Transverse aortic constriction induced the cardiac expression of profibrotic connective tissue growth factor and attenuated the expression of SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) in knockout mice, but not in controls. These genotype-dependent molecular changes were similarly prevented by eplerenone. ANP attenuated the aldosterone-induced nuclear translocation of MRs via GC-A/cGMP-dependent protein kinase I in transfected HEK 293 (human embryonic kidney) cells. Coimmunoprecipitation and fluorescence resonance energy transfer experiments demonstrated that a population of MRs were membrane associated in close interaction with GC-A and cGMP-dependent protein kinase I and, moreover, that aldosterone caused a conformational change of this membrane MR/GC-A protein complex which was prevented by ANP.
ANP counter-regulates cardiac MR activation in hypertensive heart disease. An imbalance in cardiac ANP/GC-A (inhibition) and aldosterone/MR signaling (augmentation) favors adverse cardiac remodeling in chronic pressure overload.
心房利钠肽（ANP）与肾素 - 血管紧张素 - 醛固酮系统之间的内分泌平衡对于维持动脉血压和容量稳态至关重要。本研究调查了ANP与醛固酮之间的心脏失衡（导致盐皮质激素受体（MR）信号增强）是否会导致压力超负荷时左心室不良重塑。
我们使用MR选择性拮抗剂依普利酮来测试MR在介导压力超负荷诱导的局部心脏ANP活性缺失小鼠扩张型心肌病中的作用。在进行21天的主动脉缩窄后，ANP受体（鸟苷酸环化酶[GC] - A）或下游cGMP依赖性蛋白激酶I在心肌细胞中受限制失活（敲除）的小鼠出现了左心室肥厚和纤维化增强以及收缩功能障碍。用依普利酮（100 mg/kg/d）治疗可减轻左心室肥厚，并完全预防纤维化、扩张和衰竭。主动脉缩窄诱导了敲除小鼠中促纤维化结缔组织生长因子的心脏表达，并减弱了肌浆网Ca(2+) - ATP酶（SERCA2a）的表达，但在对照小鼠中未出现这种情况。依普利酮同样预防了这些基因型依赖性分子变化。在转染的人胚肾（HEK）293细胞中，ANP通过GC - A/cGMP依赖性蛋白激酶I减弱了醛固酮诱导的MR核转位。免疫共沉淀和荧光共振能量转移实验表明，一部分MR与膜相关，与GC - A和cGMP依赖性蛋白激酶I紧密相互作用，此外，醛固酮导致这种膜MR/GC - A蛋白复合物发生构象变化，而ANP可阻止这种变化。
在高血压性心脏病中，ANP对心脏MR激活起反向调节作用。心脏ANP/GC - A（抑制）和醛固酮/MR信号（增强）之间的失衡有利于慢性压力超负荷时的不良心脏重塑。
