Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism

被引:59
作者
Cappello, Sandra
Angelone, Tommaso
Tota, Bruno
Pagliaro, Pasquale
Penna, Claudia
Rastaldo, Raffaella
Corti, Angelo
Losano, Gianni
Cerra, Maria Carmela
机构
[1] Univ Turin, Dept Neurosci, Div Physiol, I-10124 Turin, Italy
[2] Univ Calabria, Dept Pharmacobiol, Arcavacata Di Rende, Italy
[3] Univ Calabria, Dept Cell Biol, Arcavacata Di Rende, Italy
[4] Univ Turin, Dept Clin & Biol Sci, ASO San Luigi, Orbassano, Italy
[5] Ist Sci San Raffaele, Dept Biol & Technol Res, Milan, Italy
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2007年 / 293卷 / 01期
关键词
vasostatin; contractility;
D O I
10.1152/ajpheart.01352.2006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH2-terminal fragment STA-CgA(1-78) (hrSTA-CgA(1-78)), containing vasostatin-1 (CgA(1-76)) domain, exerts a negative inotropic effect and counteracts the beta-adrenergic positive inotropic effect on the rat heart. We hypothesized an involvement of nitric oxide (NO)-dependent pathway in both cardiodepression and cardioprotection by hrSTA-CgA(1-78). We also hypothesized an involvement of adenosine A(1) receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CgA(1-78). Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA(1-78) involves the G(i/o) proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA(1-78) induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NO synthase (NOS), adenosine A(1) receptor, or PKC affects hrSTACgA(1-78) protection. Using the isolated rat heart, we found that the reduction of left ventricular pressure (LVP), rate-pressure product, and maximal values of the first derivative of LVP elicited by hrSTACgA(1-78) at 33 nM is abolished by blocking G(i/o) proteins with pertussis toxin, scavenging NO with hemoglobin, and blocking NOS activity with N-G-monomethyl-L-arginine or N-5-(iminoethyl)-L-ornithine, soluble guanylate cyclase with 1H-[1,2,4] oxadiazole-[4,4-a] quinoxalin-1- one, and protein kinase (PKG) with KT5823. Data suggest the involvement of the G(i/o) proteins/NO-cGMP-PKG pathway in the hrSTA-CgA(1-78)-dependent cardioinhibition. When given before 30 min of ischemia, hrSTA-CgA(1-78) significantly reduced the size of the infarct from 64 +/- 4 to 32 +/- 3% of the left ventricular mass. This protective effect was abolished by either NOS inhibition or PKC blockade and was attenuated, but not suppressed, by the blockade of A(1) receptors. These results suggest that hrSTA-CgA(1-78) activity triggers two different pathways: one of these pathways is mediated by A(1) receptors, and the other is mediated by NO release. As with repeated brief preconditioning ischemia, hrSTA-CgA(1-78) may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.
引用
收藏
页码:H719 / H727
页数:9
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