Mazza Rosa, Gattuso Alfonsina, Mannarino Cinzia, Brar Bhawanjit K, Barbieri Sandra Francesca, Tota Bruno, Mahata Sushil K
Department of Cell Biology, University of Calabria, Arcavacata di Rende, Italy.
Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H113-22. doi: 10.1152/ajpheart.00172.2008. Epub 2008 May 9.
The catecholamine release-inhibitory catestatin [Cts; human chromogranin (Cg) A(352-372), bovine CgA(344-364)] is a vasoreactive and anti-hypertensive peptide derived from CgA. Using the isolated avascular frog heart as a bioassay, in which the interactions between the endocardial endothelium and the subjacent myocardium can be studied without the confounding effects of the vascular endothelium, we tested the direct cardiotropic effects of bovine Cts and its interaction with beta-adrenergic (isoproterenol, ISO) and endothelin-1 (ET-1) signaling. Cts dose-dependently decreased stroke volume and stroke work, with a threshold concentration of 11 nM, approaching the in vivo level of the peptide. Cts reduced contractility by inhibiting phosphorylation of phospholamban (PLN). Furthermore, the Cts effect was abolished by pretreatment with either nitric oxide synthase (N(G)-monomethyl-l-arginine) or guanylate cyclase (ODQ) inhibitors, or an ET(B) receptor (ET(BR)) antagonist (BQ-788). Cts also noncompetitively inhibited the positive inotropic action of ISO. In addition, Cts inhibited the positive inotropic effect of ET-1, mediated by ET(A) receptors, and did not alter the negative inotropic ET-1 influence mediated by ET(BR). Cts action through ET(BR) was further suggested when, in the presence of BQ-788, Cts failed to inhibit the positive inotropism of both ISO and ET-1 stimulation and PLN phosphorylation. We concluded that the cardiotropic actions of Cts, including the beta-adrenergic and ET-1 antagonistic effects, support a novel role of this peptide as an autocrine-paracrine modulator of cardiac function, particularly when the stressed heart becomes a preferential target of both adrenergic and ET-1 stimuli.
儿茶酚胺释放抑制肽抑心肽[Cts；人嗜铬粒蛋白（Cg）A（352 - 372），牛CgA（344 - 364）]是一种源自CgA的血管活性和抗高血压肽。使用离体无血管蛙心作为生物测定模型，在此模型中可研究心内膜内皮与下方心肌之间的相互作用，而不受血管内皮的干扰影响，我们测试了牛Cts的直接心肌otropic作用及其与β - 肾上腺素能（异丙肾上腺素，ISO）和内皮素 - 1（ET - 1）信号传导的相互作用。Cts剂量依赖性地降低每搏输出量和每搏功，阈值浓度为11 nM，接近该肽在体内的水平。Cts通过抑制受磷蛋白（PLN）的磷酸化来降低收缩性。此外，用一氧化氮合酶（N（G） - 单甲基 - L - 精氨酸）或鸟苷酸环化酶（ODQ）抑制剂或ET（B）受体（ET（BR））拮抗剂（BQ - 788）预处理可消除Cts的作用。Cts还非竞争性地抑制ISO的正性肌力作用。此外，Cts抑制由ET（A）受体介导的ET - 1的正性肌力作用，并且不改变由ET（BR）介导的ET - 1的负性肌力影响。当存在BQ - 788时，Cts未能抑制ISO和ET - 1刺激的正性肌力作用以及PLN磷酸化，这进一步表明了Cts通过ET（BR）发挥作用。我们得出结论，Cts的心肌otropic作用，包括β - 肾上腺素能和ET - 1拮抗作用，支持了该肽作为心脏功能自分泌 - 旁分泌调节剂的新作用，特别是当应激心脏成为肾上腺素能和ET - 1刺激的优先靶点时。
