Catestatin (human)

Background:Skin-derived antimicrobial peptides, such as human β-defensins and cathelicidins, actively contribute to host defense by inactivating microorganisms. Catestatin, a neuroendocrine peptide that affects human autonomic functions, has recently been detected in keratinocytes upon injury/infection where it inhibits the growth of pathogens. Human catestatin exhibits three single nucleotide polymorphisms: Gly364Ser, Pro370Leu, and Arg374Gln.Objective:To investigate the effects of human catestatin and its variants on keratinocyte migration and proliferation, and to elucidate the possible signaling mechanisms involved.Methods:The migration of normal human keratinocytes was analyzed using Boyden microchamber assay and in vitro wound closure assay. Cell proliferation was evaluated by BrdU incorporation, cell count assay and cell cycle analysis. Intracellular Ca(2+) mobilization was measured using a fluorescent calcium assay kit. The phosphorylation of epidermal growth factor receptor (EGFR), Akt, and MAPKs was determined by Western blotting.Results:Catestatin and its variants dose-dependently enhanced keratinocyte migration and proliferation. Moreover, catestatin peptides increased intracellular Ca(2+) mobilization and induced the phosphorylation of EGFR, Akt, extracellular signal-regulated kinase (ERK), and p38 in keratinocytes. The induction of keratinocyte migration and proliferation by catestatin peptides involved G-proteins, phospholipase C, EGFR, PI3-kinase, ERK, and p38, as evidenced by the specific inhibitory effects of pertussis toxin (G-protein inhibitor), U-73122 (phospholipase C inhibitor), AG1478 (EGFR inhibitor), anti-EGFR antibody, wortmannin (PI3-kinase inhibitor), U0126 (ERK inhibitor), and SB203580 (p38 inhibitor), respectively.Conclusion:Besides inhibiting the growth of skin pathogens, catestatin peptides may also contribute to cutaneous wound closure by enhancing keratinocyte migration and proliferation at the wound site.

Background:Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD.Methods and results:The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF. Consistent with human findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating CST as a key player in regulating hypertension. In the peripheral system, CST decreases blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla (CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels, and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways and consequent inhibition of mitochondrial permeability transition pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for a direct functional role of CST in the failing myocardium.Conclusion:These multitude of effects establish CST as a master regulator of cardiovascular functions.

In 1997, we identified a novel peptide, catestatin (CST: bovine chromogranin A [CHGA](344-364): RSMRLSFRARGYGFRGPGLQL; human CHGA(352-372): SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na(+), Ca(2+)) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G(364)S, P(370)L, and R(374)Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be "rescued" specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G(364)S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST.