Catestatin

Obesity, lipodystrophy, diabetes, and hypertension collectively constitute the main features of Metabolic Syndrome (MetS), together with insulin resistance (IR), which is considered as a defining element. MetS generally leads to the development of cardiovascular disease (CVD), which is a determinant cause of mortality and morbidity in humans and animals. Therefore, it is essential to implement and put in place adequate management strategies for the treatment of this disease. Catestatin is a bioactive peptide with 21 amino acids, which is derived through cleaving of the prohormone chromogranin A (CHGA/CgA) that is co-released with catecholamines from secretory vesicles and, which is responsible for hepatic/plasma lipids and insulin levels regulation, improves insulin sensitivity, reduces hypertension and attenuates obesity in murine models. In humans, there were few published studies, which showed that low levels of catestatin are significant risk factors for hypertension in adult patients. These accumulating evidence documents clearly that catestatin peptide (CST) is linked to inflammatory and metabolic syndrome diseases and can be a novel regulator of insulin and lipid levels, blood pressure, and cardiac function. The goal of this review is to provide an overview of the CST effects in metabolic syndrome given its role in metabolic regulation and thus, provide new insights into the use of CST as a diagnostic marker and therapeutic target.

Catestatin is a 21-amino acid residue, cationic and hydrophobic peptide that is formed endogenously by proteolytic cleavage of its precursor chromogranin A, a major protein co-stored and co-released with catecholamines from the storage vesicles in adrenal chromaffin cells and adrenergic neurons. This peptide exhibits potent catecholamine release-inhibitory activity by acting on the neuronal nicotinic acetylcholine receptor. It also stimulates histamine release from mast cells via heterotrimeric G-proteins in a receptor-independent manner. Plasma levels of catestatin are diminished not only in hypertensive patients but also in their still-normotensive offspring, indicating its role in the pathogenesis of hypertension. Consistently, exogenous catestatin rescues hypertension in chromogranin A knockout mice and diminishes blood pressure responses to activation of sympathetic outflow in rats. These hypotensive actions of catestatin may be caused directly by autocrine inhibition of catecholamine release from the sympathoadrenal system and indirectly by paracrine stimulation of the potent vasodilator histamine release from mast cells. Recently, three human variants of catestatin displaying differential potencies for inhibition of catecholamine secretion have been identified. One of these variants (Gly364Ser) causes increased baroreceptor sensitivity, increased cardiac parasympathetic activity, and decreased cardiac sympathetic activity, and it seems to alter the risk for hypertension. These cardiovascular effects may have resulted by action of this peptide in the baroreceptor centre of the nucleus tractus solitarius. Thus, accumulating evidence documents the endogenous peptide catestatin as a novel regulator of cardiac function and blood pressure.

Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.