Reverse myocardial effects of intermedin in pressure-overloaded hearts: role of endothelial nitric oxide synthase activity
Reverse myocardial effects of intermedin in pressure-overloaded hearts: role of endothelial nitric oxide synthase activity
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DOI：
10.1113/jphysiol.2012.240812
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发表时间：
2013-02-01
影响因子：
5.5
通讯作者：
Leite-Moreira, Adelino F.
中科院分区：
文献类型：
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作者：
Pires, Ana Luisa;Pinho, Marta;Leite-Moreira, Adelino F.
中间肽（IMD）是以前体形式合成的心脏肽，其经历一系列蛋白水解裂解和酰胺化以产生47个氨基酸（IMD 147）和40个氨基酸（IMD 847）的活性形式。有几条证据表明IMD在心脏病大鼠模型中的表达增加，包括充血性心力衰竭和缺血;然而，其对心脏病的心肌影响尚未研究。考虑到这一点，我们研究了增加IMD 147浓度的直接影响。（1010 - 106 m）对两种慢性压力超负荷大鼠模型左心室（LV）乳头肌收缩和舒张的影响，一种由横向主动脉缩窄（TAC）引起，另一种由慢性NO合酶抑制引起的一氧化氮（NO）缺乏引起（NG-硝基-L-精氨酸，l-NAME）和相应的对照（假手术组和对照组）。在TAC和l-NAME大鼠中，外源性给予IMD 147引起浓度依赖性正性肌力作用和Lustropic作用。相比之下，在Sham和Ctrl大鼠中，IMD 147诱导负性变力性反应，而对松弛无显著影响。TAC和L-NAME大鼠均表现出左室肥厚、左室收缩压升高、收缩功能保留和过氧亚硝酸盐水平升高。在正常心肌（对照组和假手术组）中，IMD 147诱导内皮型一氧化氮合酶（eNOS）丝氨酸1177磷酸化增加3倍，表明eNOS活性增强。在TAC和l-NAME大鼠中，eNOS磷酸化在基线时增加，其对IMD 147的反应减弱。此外，对IMD 147的不同心肌反应伴随着不同的亚细胞机制。而在Sham大鼠中，添加IMD 147诱导了由于NO/cGMP活化的心肌肌钙蛋白I的磷酸化，在TAC大鼠中，IMD 147诱导了可能与cAMP/蛋白激酶A活化相关的受磷蛋白磷酸化。因此，我们第一次证明了逆转心肌反应IMD 147神经体液刺激由于损害的eNOS激活在TAC和L-NAME大鼠。这些结果不仅揭示了正常和肥厚心脏中IMD 147的不同心肌效应和亚细胞机制，而且突出了心脏内皮功能障碍在神经体液心肌作用中的潜在病理生理学相关性。
Intermedin (IMD) is a cardiac peptide synthesized in a prepro form, which undergoes a series of proteolytic cleavages and amidations to yield the active forms of 47 (IMD147) and 40 amino acids (IMD847). There are several lines of evidence of increased IMD expression in rat models of cardiac pathologies, including congestive heart failure and ischaemia; however, its myocardial effects upon cardiac disease remain unexplored. With this in mind, we investigated the direct effects of increasing concentrations of IMD147 (1010 to106m) on contraction and relaxation of left ventricular (LV) papillary muscles from two rat models of chronic pressure overload, one induced by transverse aortic constriction (TAC), the other by nitric oxide (NO) deficiency due to chronic NO synthase inhibition (NG-nitro-l-arginine, l-NAME), and respective controls (Sham and Ctrl). In TAC and l-NAME rats, exogenous administration of IMD147 elicited concentration-dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD147 induced a negative inotropic response without a significant effect on relaxation. Both TAC and l-NAME rats presented LV hypertrophy, elevated LV systolic pressures, preserved systolic function and elevated peroxynitrite levels. In the normal myocardium (Ctrl and Sham), IMD147 induced a 3-fold increase of endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177, indicating enhanced eNOS activity. In TAC and l-NAME rats, eNOS phosphorylation was increased at baseline, and its response to IMD147 was blunted. In addition, the distinct myocardial response to IMD147 was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD147 induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD147 induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD147 neurohumoral stimulation due to impairment of eNOS activation in TAC and l-NAME rats. These results not only reveal the distinct myocardial effects and subcellular mechanisms for IMD147 in normal and hypertrophic hearts, but also highlight the potential pathophysiological relevance of cardiac endothelial dysfunction in neurohumoral myocardial action.