Catestatin (CST) is a key mediator of the immunoendocrine regulation of cardiovascular function

Objective: Hypertension (HTN) is a global pandemic, affecting more than one billion people. Although catestatin (CST), a chromogranin A (CgA)-derived peptide, decreases blood pressure (BP) in rodent models of HTN, the mechanisms underlying its hypotensive action is yet to be established. Here we generated CST knockout (CST-KO) mice to pinpoint the mechanism of the hypotensive action of CST. Methods and Results: CST-KO mice were hypertensive; their serum cytokines were elevated, anti-inflammatory genes were downregulated, and their hearts showed marked infiltration with macrophages. CST replenishment reversed all these phenotypes. It normalized BP, reduced serum cytokines, upregulated anti-inflammatory genes, and reduced the cardiac infiltrates by approx 30%, as determined by FACS. Pre-conditioning-induced cardioprotection was also abolished in CST-KO mice. We hypothesize that anti-hypertensive and cardioprotective effects of CST may be caused by suppressed trafficking of macrophages to the heart and reduced inflammation. Such cause-and-effect relationship is supported by the fact that CST-KO mice became normotensive when they were depleted of macrophages using chlodronate, or when they received bone marrow transplant from wild-type littermates. Mechanistically, cardiac tissue transcriptomes revealed multiple altered gene expression programs in CST-KO mice that are commonly encountered in human cardiomyopathies. Among others, a prominent reduction of Glo1 gene was seen in CST-KO mice; supplementation with CST increased it expression by mora than 7-fold. Because Glo1 in macrophages metabolizes methylglyoxal, an inflammatory agent whose accumulation promotes vascular damage in HTN and T2DM, this could be one of the means by which CST attenuates inflammation and improves cardiovascular health. Repletion of CST also improved glucose metabolism and increased the surface area of mitochondrial cristae and decreased the secretion of catecholamines; the latter explains the anti-hypertensive actions of CST. Conclusions: We conclude that the anti-hypertensive effects of CST is mediated at least in part via anti-inflammatory actions of CST; in the absence of CST, macrophages are more reactive, they infiltrate the heart and alter the ultrastructure, physiologic and molecular makeup of the myocardium. These studies implicate CST as a key mediator of the observed crosstalk between systemic and cardiac inflammation in HTN.