期刊
ENDOCRINOLOGY
卷 149, 期 10, 页码 4780-4793出版社
ENDOCRINE SOC
DOI: 10.1210/en.2008-0318
关键词
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资金
- Fondazione Cassa di Risparmio di Calabria e Lucania
- Ministero dell'lstruzione e dell'Universita
- Dottorato di Fisiologia
- University of Turin
- Istituto Nazionale di Ricerca Cardiovascolare
- Compagnia San Paolo
- National Institutes of Health and Department of Veterans Affairs [R01 DA011311, P01 HL58120]
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.
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