The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism
The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism
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DOI：
10.1210/en.2008-0318
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Cerra, Maria Carmela
中科院分区：
文献类型：
--
作者：
Angelone, Tommaso;Quintieri, Anna Maria;Cerra, Maria Carmela
原发性高血压患者血浆中的循环catestatin（Cts;人嗜铬粒蛋白A（352-372））水平降低。小鼠嗜铬粒蛋白A（Chga）基因的遗传切除增加了血压，用CTS预处理Chga缺失小鼠可防止血压升高，表明CTS在预防高血压中的直接作用。这种显著的血管反应性促使我们测试野生型（WT）Cts和天然存在的人类变体（G364 S-Cts和P370 L-Cts）对心肌和冠状动脉功能的直接心血管作用和作用机制。使用Langendorff灌注的大鼠心脏测定WT-Ct和人变体的直接心血管作用。WT-Cts剂量依赖性地增加心率和冠状动脉压力，降低左心室压力、心率压力乘积和正和负LVdP/dt。WT-Cts不仅能抑制受磷蛋白磷酸化，而且其变力性和减力性作用可被β（2）-肾上腺素能受体、Gi/o蛋白、一氧化氮或cGMP的化学抑制作用所消除，表明WT-Cts参与了β（2）-肾上腺素能受体-Gi/o蛋白-一氧化氮-cGMP信号传导机制。与此相反，G364 S-Cts不影响基础心脏性能，但取消异丙肾上腺素诱导的正性肌力和lusitropism。P370 L-Cts降低心率-血压乘积，仅抑制异丙肾上腺素诱导的正性肌力和向左收缩70%。Cts也抑制内皮素-1诱导的正性肌力和冠脉收缩。两者合计，对基础机械性能施加的心脏抑制影响和对β-肾上腺素能和内皮素-1刺激的反调节作用指向CTS作为一种新型心脏调节剂，能够保护心脏免受过度交感嗜铬过度激活，例如高血压性心肌病。
Circulating levels of catestatin (Cts; human chromogranin A(352-372)) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation, indicating a direct role of Cts in preventing hypertension. This notable vasoreactivity prompted us to test the direct cardiovascular effects and mechanisms of action of wild-type (WT) Cts and naturally occurring human variants (G364S-Cts and P370L-Cts) on myocardial and coronary functions. The direct cardiovascular actions of WT-Cts and human variants were determined using the Langendorff-perfused rat heart. WT-Cts dose-dependently increased heart rate and coronary pressure and decreased left ventricular pressure, rate pressure product and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation, but also the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of beta(2)-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of beta(2)-adrenergic receptors-Gi/o protein-nitric oxide-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased rate pressure product and inhibited only isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1-induced positive inotropism and coronary constriction. Taken together, the cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against beta-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.