The Antihypertensive Chromogranin A Peptide Catestatin Acts as a Novel Endocrine/Paracrine Modulator of Cardiac Inotropism and Lusitropism

Rationale:The neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone.Objective: Catestatin shares several functions with angiogenic factors. We therefore reasoned that catestatin induces growth of new blood vessels. Methods and Results:Catestatin induced migration, proliferation, and antiapoptosis in endothelial cells and exerted capillary tube formation in vitro in a Matrigel assay, and such effects were mediated via G protein, mitogen-activated protein kinase, and Akt. Catestatin-induced endothelial cell functions are further mediated by basic fibroblast growth factor, as shown by blockade of effects by a neutralizing fibroblast growth factor antibody. Furthermore, catestatin released basic fibroblast growth factor from endothelial cells and stimulated fibroblast growth factor signaling. In addition to its function on endothelial cells, catestatin also exerted effects on endothelial progenitor cells and vascular smooth muscle cells. In vivo, catestatin induced angiogenesis in the mouse cornea neovascularization assay and increased blood perfusion and number of capillaries in the hindlimb ischemia model. In addition to angiogenesis, catestatin increased density of arterioles/arteries and incorporation of endothelial progenitor cells in the hindlimb ischemia model, indicating induction of arteriogenesis and postnatal vasculogenesis. Conclusion:We conclude that catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. (Circ Res. 2010;107:1326-1335.) Key Words: angiogenesis Ⅲ blood vessels Ⅲ endothelium Ⅲ endothelial progenitor cells C hromogranin (Cg)A, the index member of the chromogranin/secretogranin protein family, is the major soluble protein of catecholamine storage vesicles of sympathetic nerve terminals and the adrenal medulla. 1,2 CgA is a proprotein giving rise to biological active peptides like the dysglycemic hormone pancreastatin, 3 the vasodilator vasostatin, 4 and catestatin 5 (CST) ), which inhibits catecholamine release by acting as a nicotinic cholinergic antagonist, resulting in a negative-feedback mechanism. Although plasma CgA is high in human essential (hereditary) hypertension, the plasma concentration of CST is lower in both established cases and in normotensive subjects with a family history of the disease, 6 suggesting a mechanism whereby diminished CST might increase the risk for later development of hypertension. Consistent with the human findings, high blood pressure has been reported in mice after targeted ablation of the Chga gene (Chga knockout), and such high blood pressure can be "rescued" either by replacement with CST or introduction of the human ortholog in the Chga knockout background. 7 Angiogenesis, the growth of new vessels from the preexisting vasculature, is an important process in many physiological conditions including embryonic development and wound healing. However, defects in the regula- Original received February 25, 2010; revision received September 27, 2010;...

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“…CST acts as a negative regulator of hypertension, 7 inotropy, and lusitropy. 20 CST Figure 6. CST-induced effects on ECs are mediated by bFGF.…”

Section: Discussionmentioning

confidence: 99%

The Neuropeptide Catestatin Acts As a Novel Angiogenic Cytokine via a Basic Fibroblast Growth Factor–Dependent Mechanism

Theurl

Schgoer

Albrecht

et al. 2010

Circulation Research

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“…Moreover, in order to evaluate the effective role of CST in cardioprotection, in additional experiments, hearts were perfused with heat-inactivated CST [3] at the identical concentration of active CST (75nM), for 20-min at the beginning of reperfusion.…”

Section: Additional Experimentsmentioning

confidence: 99%

“…Actually, CST is known to counteract exaggerated β-adrenergic activity, which is relevant part of the neuroendocrine scenario of heart failure [1][2][3][4], and to dilate human vessels in vivo [16], thus exerting positive effects on cardiac afterload. In line with these evidences and since β-blockade is largely used as post-ischaemic treatment, the present work suggests that exogenous CST may provide new tool for pharmacological postconditioning.…”

Section: Clinical Considerationsmentioning

confidence: 99%

“…Recently, on the isolated rat heart, CST was found to elicit a vasorelaxant influence on coronary arteries pre-contracted by endothelin-1, together with negative inotropic and lusitropic actions, counteracting the positive effects elicited by the β-adrenoceptor activator, isoproterenol [3]. CST inhibition of β-adrenoceptor activation in cardiomyocytes [3] is "presumably mediated by the relaxing effect of the endothelial cell-derived NO-release mediated by Akt/PKB signalling to endothelial NO synthase" [19]. Importantly, in AMI patients an initial reduction with a subsequent increase in CST plasma levels has been recently reported [55].…”

Section: Introductionmentioning

confidence: 99%

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Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Perrelli

Tullio

Angotti

et al. 2013

Pflugers Arch - Eur J Physiol

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Aims: Catestatin (CST) limits myocardial ischaemia/reperfusion (I/R) injury with unknown mechanisms. Clearly phosphoinositide-3-kinase (PI3K), protein-kinase-C (PKC) isoforms, including intra-mitochondrial PKCε, mitochondrial-K ATP (mitoK ATP ) channels and subsequent reactiveoxygen-species (ROS)-signalling play important roles in postconditioning cardioprotection, preventing mitochondrial permeability transition pore (mPTP) opening. Therefore, we studied the role of these extra-and intra-mitochondrial factors in CST-induced protection. Methods and Results: Isolated rat hearts and H9c2 cells underwent I/R and oxidative stress, respectively. In isolated hearts CST (75nM, CST-Post) given in early-reperfusion significantly reduced infarct-size, limited post-ischaemic contracture, and improved recovery of developed left ventricular pressure.PI3K inhibitor, LY-294002 (LY), large spectrum PKC inhibitor, Chelerythrine (CHE), specific PKCε inhibitor (εV1-2), mitoK ATP channel blocker, 5-Hydroxydecanoate (5HD) or ROS scavenger, 2-mercaptopropionylglycine (MPG) abolished the infarct-sparing effect of CST. Notably the CSTinduced contracture limitation was maintained during co-infusion of 5HD, MPG or εV1-2, but it was lost during co-infusion of LY or CHE. In H9c2 cells challenged with H 2 O 2 , mitochondrialdepolarization (an index of mPTP-opening studied with JC1-probe) was drastically limited by CST (75nM). Conclusions: Our results suggest that the protective signalling pathway activated by CST includes mitoK ATP channels, ROS-signalling and prevention of mPTP opening, with a central role for upstream PI3K/Akt and PKCs. In fact, all inhibitors completely abolished CST-infarct-sparing effect. Since CST-anti-contracture effect cannot be explained by intra-mitochondrial mechanisms (PKCε activation and mitoK ATP channel opening) or ROS-signalling, it is proposed that these downstream signals are part of a reverberant loop which re-activates upstream PKCs, which therefore play a pivotal role in CST-induced protection.

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“…[30] Catestatin is the first known endogenous compound able to inhibit in vitro catecholamine release from both chromaffin cells and noradrenergic neurons by acting as a non-competitive nicotinic cholinergic antagonist. [31] Angelone et al, (2008) [32] hypothesized that circulating levels of catestatin decreased in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation indicating a direct role of Cts in preventing hypertension.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic Effects of Local Anesthesia and its Possible Correlation with Chromogranin A

Al-Saffar¹,

Al–Sandook²,

Taha³

2014

AJPS

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Aim: To study the effects of local anesthesia on blood pressure in patients undergo extraction of maxillary teeth under infiltration local anesthesia and to compare the level of salivary chromogranin A before and after administration of local anesthesia and its possible correlation with hemodynamic effects of local anesthesia. Materials and Methods: A total of 26 patients (18 female, 8 male) who need tooth extraction under infiltration local anesthesia were examined in two situations (pre and post local anesthetic administration). For each patient salivary sample was collected by salivette to estimate the level of chromogranin A using ELISA Kits. For all patients, the blood pressure and pulse rate were measured before and after administration of local anesthesia using automatic blood pressure recorder. Results: the results showed significant differences between salivary chromogranin A for patients before the administration of local anesthesia (580.33 ± 130.42) ng/ml and after the administration of local anesthesia (674.51+ 130.93) ng/ml with p < 0.05. The results also showed that the mean value of blood pressure (systolic and diastolic blood pressure) lowered after administration of local anesthesia but with no significant differences (p > 0.05) with pre -local anesthetic value. The pulse rate was increase in it is value after local anesthetic administration with a significant differences (p < 0.05) than pre -anesthetic value. Conclusions: tooth extraction and administration of infiltration local anesthesia caused hypotension with no significant effect (p > 0.05) while it caused increase in pulse rate with a significant effect (p < 0.05). Administration of infiltration local anesthesia caused significant effects on salivary chromogranin A levels, also this study showed that there was significant inverse correlation between systolic blood pressure and chromogranin A levels(p < 0.05) after administration of infiltrations local anesthesia during dental treatments (tooth extraction).

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The Antihypertensive Chromogranin A Peptide Catestatin Acts as a Novel Endocrine/Paracrine Modulator of Cardiac Inotropism and Lusitropism

Cited by 141 publications

References 51 publications

The Neuropeptide Catestatin Acts As a Novel Angiogenic Cytokine via a Basic Fibroblast Growth Factor–Dependent Mechanism

The Neuropeptide Catestatin Acts As a Novel Angiogenic Cytokine via a Basic Fibroblast Growth Factor–Dependent Mechanism

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Hemodynamic Effects of Local Anesthesia and its Possible Correlation with Chromogranin A

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