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Department of Pharmaceutical Sciences Massachusetts College of Pharmacy and Health Sciences Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Ahmmed Ally, M.D., Ph.D., Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. E-mail: Ahmmed.Ally{at}mcphs.edu.
Chromogranin A (CHGA) is a 48-kDa polypeptide that is stored and released with catecholamines from secretory vesicles in adrenal medulla and postganglionic sympathetic axons (1, 2). CHGA plays a significant role in various intracellular functions, such as formation of secretory granules and sequestration of hormones in neuroendocrine cells (3). In addition, CHGA can be converted to other bioactive peptides via posttranslational proteolytic processing (4). Thus, CHGA may play numerous roles in endocrine, cardiovascular, and nervous systems.
CHGA may get converted into the following peptides: pancreastatin (5), vasostatins I and II (6), and catestatin (Cts) (4, 7, 8, 9, 10, 11). These peptides influence the autocrine, paracrine, and endocrine functions in various ways. In hypertensive patients, the levels of CHGA are elevated, whereas the expression of Cts is attenuated (12, 13). This important discovery has tremendous potential with regards to the development of therapeutic agents targeted at Cts for the treatment of hypertension. In addition, the abolishment of CHGA expression may cause initiation of hypertension which could be possibly treated by delivery of catestatin (1, 14).
Studies have demonstrated that Cts causes inhibition of catecholamine release from sympathoadrenal chromaffin cells by blocking the neuronal nicotinic cholinergic receptors (9, 15). In addition, it prevents the desensitization of the release of catecholamines from chromaffin cells that is initially caused due to continuous stimulation of nicotinic receptors (16). Cts may also stimulate circulating levels of histamine and epinephrine, causing vasodilatation (17). Three naturally occurring amino acid variants have been identified in the Cts region of CHGA: Pro370 Leu (P370L), Arg374Gln (A374G), and Gly364Ser (G364S); of these, the first two are relatively rare (10, 18).
The paper by Angelone et al. (19) investigates and describes the effect of Cts and its variants on different cardiac parameters under normal as well as hypertensive conditions. This study may be significant in further understanding the mechanisms involved in cardiotropism exhibited by Cts. The methodology involves Langendorff perfused rat heart and the study analyzed the effect of Cts and its variants on positive cardiotropic actions induced by agents under a wide variety of conditions. Two cardiotropic principles have been evaluated: inotropism (force of myocardial contraction) and lusitropism (myocardial relaxation). Cts seems to increase heart rate, half-time relaxation, and coronary pressure and to inhibit myocardial parameters such as left ventricular pressure, rate-pressure product, and maximum rate of left ventricular pressure, all of which are attenuated under basal conditions. Thus, Cts exhibits negative inotropic and lusitropic actions via various signaling molecules such as adrenergic (β1/β2 and 
) and cholinergic receptors, Gi/o proteins, nitric oxide synthase (NOS)-nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway and endothelin-1 (ET-1).
The results indicate that the negative cardiotropic effects of Cts may be obliterated in the presence of β1/β2 receptor antagonists and pretreatment with Gi/o inhibitor. In addition, -receptor antagonists may attenuate the cardio-suppressive effects of Cts. However, the parameters are unaffected by antagonism of muscarinic cholinergic receptors. These findings indicate other possible mechanisms of action of Cts that have been earlier found to interact with nicotinic cholinergic receptors (9, 15). It is not clear whether these effects are directly or indirectly receptor mediated because there is no information about receptor binding studies with respect to Cts. The possibility of a cross talk between the various receptor-mediated pathways needs to be investigated further.
NO has an inhibitory effect on contractility by reducing L-type Ca2+ current (20). The annihilation of negative cardiotropic effects of Cts in the presence of a NO scavenger has been reported in the paper. However, these actions of Cts are unaffected by nonspecific NOS inhibitors. The study further investigates the effect of selective inhibitors of endothelial and neuronal NOS and reports the involvement of endothelial NOS in the cardiac functions of Cts. The paper demonstrates the inhibition of phosphorylation of phospholamban, protein kinase B, glycogen synthase kinase-3 and ERK1/2 by Cts, and demonstrates significant interactions between Cts and various intracellullar signal transduction mechanisms. These findings further clarify the submechanisms of Cts and establish an interactive connection between various pathways that play an important role on eliciting the negative cardiotropism of Cts. This strengthens the hypothesis that Cts may serve as a novel target for the treatment of hypertension. Agents that would influence the expression and function of Cts need to be developed and evaluated using both in vivo and in vitro models of hypertension.
The authors have made a commendable effort in evaluating and comparing the effect of two Cts variants; P370L and G364S, with wild-type Cts (wt-Cts), which may be significant from the pharmacogenomic point of view. The study determines and reports the relative potency of Cts and its variants with respect to basal conditions, counteraction of isoproterenol-mediated positive cardiotropism and reduction of contractility induced by ET-1. In all investigated situations, wt-Cts seems to be the most potent. This may be correlated with the fact that Cts variants differentially influence nicotine-evoked catecholamine secretion (2). However, the effect of the Cts variants on other pathways that may be involved in its cardio-suppressive functions needs to be investigated. The role of the Cts variant, A374G, on various cardiac parameters with respect to the negative cardiotropism of wt-Cts still remains unexplored.
In conclusion, the experiments performed in the study determine the actions of Cts on various cardiac parameters under different conditions. Taking the advantage of the cardioprotective effects of Cts, further studies are important and relevant that will lead to the development of drugs for the treatment of hypertension, a disease affecting billions of people in this world.
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Footnotes |
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Abbreviations: CHGA, Chromogranin A; Cts, catestatin; ET-1, endothelin-1; NO, nitric oxide; NOS, NO synthase; wt-Cts, wild-type Cts.
Received June 10, 2008.
Accepted for publication June 19, 2008.
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References |
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 Top References |
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S, Mutt V, Makk G, Feistner GJ, Barchas JD 1986 Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Nature 324:476–478[CrossRef][Medline]
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