Catestatin regulates core bioenergetic and metabolic functions of the myocardium

OBJECTIVE: Hypertension is a global pandemic, affecting more than one billion people. We have recently reported that chromogranin A (CgA) peptide catestatin (CST: human CgA352-372 ) decreases blood pressure in hypertensive CST knockout (CST-KO) mice by inhibiting catecholamine secretion and decreasing inflammation. Using CST-KO mice we show here that CST regulates core bioenergetic and metabolic functions of the myocardium. METHODS AND RESULTS: We carried out transcriptomic analyses (gene microarray) of the left ventricles of wild-type (WT) and CST-KO mice. Analysis revealed altered expression. Downregulated genes, which were most enriched in pathways that impact muscle conduction and contractility include, among other genes, Glo1 (glyoxylase 1). Upregulated genes include, among others, Gm7120 (predicted gene 7120), Astn2 (astrotactin 2), and Defa20 (defensin a-20). We validated several of these up- and downregulated genes by qPCR and found that CST supplementation reversed these aberrant expressions in all cases. Targeted qPCR analysis of sarcomeric genes revealed reduced expression of Tnni3 (cardiac troponin I), Tnnt2 (cardiac troponin T), Myl4(atrial light chain-1) and Myl7 (atrial light chain-2) genes in CST-KO mice. CST treatment increased expression of Tnni3, Tnnt2, Actc1 (cardiac a-actin), Myl4 and Myl7 in both WT and CST-KO mice albeit to a much higher level in CST-KO mice. An analysis of mitochondrial genes revealed reduced expression of Ndufa3 (complex I), Sdhc (complex II) and Atp5j (complex V) genes in CST-KO mice. CST treatment increased the expression of all three genes in WT and CST-KO mice. Taken together, these unbiased approaches and qPCR validation studies provide insight into how an inflamed dysfunctional heart in the absence of CST may impact muscle function (contractility), rhythm, mitochondrial bioenergetics, and conduction. CST-KO mice showed decreased uptake of 2-deoxy glucose in the left ventricle compared to WT mice. Furthermore, glucose-6-phosphate utilization was significantly lower in CST-KO compared to WT mice. We also found that compared to WT mice, CST-KO mice show a significantly higher uptake of fatty acids. Furthermore, 14 C-labeled acid soluble metabolites were significantly higher in CST-KO compared to WT mice, suggesting that increased dependence on fatty acids for energy needs make CST-KO hearts resistant to insulin. CONCLUSIONS: Taken together with the cardiometabolic shifts (decreased glucose utilization with a concomitant increase in the utilization of fatty acids), these findings indicate that CST maintains cardiometabolic homeostasis; it does so at least in part by acting as an insulin-sensitizing peptide which regulates myocardial choice of substrates for generating energy (i.e., ATP). © FASEB.