The antihypertensive chromogranin A peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism

Circulating levels of catestatin (Cts: human chromogranin A352-372) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pre-treatment 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 Cts (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 (LVP), rate pressure product (RPP) and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation but the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of β2-adrenergic receptors (AR), Gi/o protein, nitric oxide (NO), or cGMP indicating involvement of β2-ARs-Gi/o protein-NO-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased RPP and only inhibited isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1 (ET-1)-induced positive inotropism and coronary constriction. Taken together, the cardio-inhibitory influence exerted on basal mechanical performance and the counter-regulatory action against beta-adrenergic and ET-1 stimulations, point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin over-activation, e.g. hypertensive cardiomyopathy.