The physiological anti-hypertensive peptide catestatin and its common human variant Gly364Ser: differential cardiovascular effects in a rat model of hypertension

Abstract

Catestatin (CST), a 21-amino acids physiological peptide, has emerged as a key modulator of cardiovascular functions due to its anti-hypertensive and cardioprotective properties. However, the ramifications of the most common human variant of CST (viz. Gly364Ser) on cardiovascular pathophysiology remain partially understood. In this study, hypertension was induced in uninephrectomized rats by treatment with deoxycorticosterone-acetate and sodium chloride (DOCA-salt). The DOCA-salt-induced hypertensive (DSHR) animals were then intraperitoneally administered with either CST wild-type (CST-WT) or 364Ser variant (CST-Ser) peptide. CST-Ser was profoundly less effective than CST-WT in rescuing the elevated systolic blood pressure [from ~211 mmHg to ~176 mmHg, p<0.0001 (CST-Ser) versus ~116 mmHg, p<0.0001 (CST-WT)] and heart rate [from ~356 bpm to ~314 bpm, p=0.66 (CST-Ser) versus ~276 bpm, p=0.02 (CST-WT)]. CST-Ser also showed diminished effects in lowering diastolic blood pressure and mean arterial pressure in the DSHR animals. Furthermore, CST-Ser was inefficient/markedly less potent in rescuing the impaired contractile and diastolic function in DSHR animals [improvements in the contractility index by ~22 s–1 (CST-Ser), p=0.15 versus by ~84 s–1 (CST-WT), p<0.0001 and decrease in end-diastolic pressure by ~4 mmHg (CST-Ser), p=0.015 versus by ~14 mmHg (CST-WT), p<0.0001]. Moreover, CST-Ser exerted less potent anti-inflammatory effects on the DSHR hearts than CST-WT. These findings are in concordance with the elevated systolic/diastolic blood pressure observed in Ser variant carriers from various human populations. This study provides compelling evidence for the diminished anti-hypertensive and cardioprotective effects of the CST-Gly364Ser variant.