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Catestatin (CST) is a bioactive cleavage product of the neuroendocrine prohormone chromogranin A (CgA). Recent findings show that CST can exert anti-inflammatory and antiadrenergic effects by suppressing the inflammatory actions of mammalian macrophages. However, recent findings also suggest that macrophages themselves are major CST producers. Here, we hypothesize that macrophages produce CST in an inflammation-dependent manner and thereby might self-regulate inflammation in an autocrine fashion. CST is associated with pathological conditions hallmarked by chronic inflammation, including autoimmune, cardiovascular, and metabolic disorders. Since intraperitoneal injection of CST in mouse models of diabetes and inflammatory bowel disease has been reported to be beneficial for mitigating disease, we posit that CST should be further investigated as a candidate target for treating certain inflammatory diseases. Catestatin (CST), a 21-amino acid peptide derived from proteolytic cleavage of the prohormone chromogranin A, has been reported to have anti-inflammatory and antiadrenergic functions in mice. CST is thought to be mainly co-released with catecholamines by neuroendocrine cells. Recent studies suggest that macrophages are also a source of CST and that the anti-inflammatory effects of CST might be attributable to CST produced by macrophages, at least in mice. We propose that CST produced by macrophages might suppress neuronal and neuroendocrine activity, in an inflammation-dependent manner. [ABSTRACT FROM AUTHOR]

Highlights • We modeled chronic constriction injury (CCI) rats to simulate neuropathic pain (NPP) condition. • Upregulated purinergic P2X 4 receptor was accompanied with elevated hyperalgesia. • Catestatin (CST) aggravated NPP by activating P2X 4 in spinal microglia. • This regulation of CST depended on the activation of the MAPK-ERK1/2 signaling pathway. Abstract Neuropathic pain is defined as a type of chronic pathological pain that often results from nerve damage or disease. The purinergic receptor P2X 4 is mainly expressed on the cell surface of spinal dorsal horn microglia and is known to be involved in neuropathic pain. Catestatin (CST) is an endogenous peptide derived from chromogranin A. Here, we attempted to identify how CST function in neuropathic pain. Rat model of chronic constriction injury (CCI) was used and experimental results indicated that mechanical and thermal pain sensitivities were significantly increased in CCI rats. The group of CCI rats that received intrathecal CST injection (CCI + CST) exhibited higher P2X 4 mRNA and protein levels compared with the CCI group. Moreover, the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) in the CCI + CST group was higher than in the CCI group. This suggested that CST might aggravate neuropathic pain by enhancing P2X 4 receptor expression in spinal microglia, and that the ERK1/2 pathway might be key in the development of neuropathic pain. [ABSTRACT FROM AUTHOR]

The granin family comprises altogether 7 different proteins originating from the diffuse neuroendocrine system and elements of the central and peripheral nervous systems. The family is dominated by three uniquely acidic members, namely chromogranin A (CgA), chromogranin B (CgB) and secretogranin II (SgII). Since the late 1980s it has become evident that these proteins are proteolytically processed, intragranularly and/or extracellularly into a range of biologically active peptides; a number of them with regulatory properties of physiological and/or pathophysiological significance. The aim of this comprehensive overview is to provide an up-to-date insight into the distribution and properties of the well established granin-derived peptides and their putative roles in homeostatic regulations. Hence, focus is directed to peptides derived from the three main granins, e.g. to the chromogranin A derived vasostatins, betagranins, pancreastatin and catestatins, the chromogranin B-derived secretolytin and the secretogranin II-derived secretoneurin (SN). In addition, the distribution and properties of the chromogranin A-derived peptides prochromacin, chromofungin, WE14, parastatin, GE-25 and serpinins, the CgB-peptide PE-11 and the SgII-peptides EM66 and manserin will also be commented on. Finally, the opposing effects of the CgA-derived vasostatin-I and catestatin and the SgII-derived peptide SN on the integrity of the vasculature, myocardial contractility, angiogenesis in wound healing, inflammatory conditions and tumors will be discussed. [ABSTRACT FROM AUTHOR]

Catestatin (CST), a fragment of Chromogranin-A, exerts angiogenic, arteriogenic, vasculogenic and cardioprotective effects. CST is a very promising agent for revascularization purposes, in “NO OPTION” patients. However, peptides have a very short half-life after administration and must be conveniently protected. Fibronectin-coated pharmacologically active microcarriers (FN-PAM), are biodegradable and biocompatible polymeric microspheres that can convey mesenchymal stem cell (MSCs) and therapeutic proteins delivered in a prolonged manner. In this study, we first evaluated whether a small peptide such as CST could be nanoprecipitated and incorporated within FN-PAMs. Subsequently, whether CST may be released in a prolonged manner by functionalized FN-PAMs (FN-PAM-CST). Finally, we assessed the effect of CST released by FN-PAM-CST on the survival of MSCs under stress conditions of hypoxia-reoxygenation. An experimental design, modifying three key parameters (ionic strength, mixing and centrifugation time) of protein nanoprecipitation, was used to define the optimum condition for CST. An optimal nanoprecipitation yield of 76% was obtained allowing encapsulation of solid CST within FN-PAM-CST, which released CST in a prolonged manner. In vitro , MSCs adhered to FN-PAMs, and the controlled release of CST from FN-PAM-CST greatly limited hypoxic MSC-death and enhanced MSC-survival in post-hypoxic environment. These results suggest that FN-PAM-CST are promising tools for cell-therapy. [ABSTRACT FROM AUTHOR]

Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21–4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85–19.05] vs. 9.65 [6.37–12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = −0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted. [Display omitted] • CBD supplementation reduces office blood pressure (BP) and serum catestatin levels. • The extent of BP reduction correlates with the reduction in serum catestatin levels. • Baseline catestatin levels may predict the extent of CBD-associated BP reduction. [ABSTRACT FROM AUTHOR]

Catestatin (CST) is a proteolytic fragment of Chromogranin A with a broad spectrum of activities in the cardiovascular system. The level of plasma CST increases in chronic heart failure patients, but its potential relationship to patient prognosis is unknown. In this study, we measured plasma CST levels in 202 chronic heart failure patients and followed them for a median of 52.5 months. The plasma CST level was higher in patients with all-cause death and cardiac death than in survivors. According to univariate COX regression, higher plasma CST levels predicted increased risk of all-cause and cardiac death. After adjustment for other confounding factors, plasma CST was an independent risk factor for both outcomes, and the hazard ratios (HRs) were 1.84 (95% CI: 1.02–3.32, p = 0.042) and 2.41 (95% CI: 1.26–4.62, p = 0.008) for all-cause death and cardiac death, respectively. The new risk-predictive model considering CST was superior to the previous model for both outcomes by ANOVA and likelihood ratio tests (p = 0.040 and p = 0.008, respectively). Concurrent increases in plasma BNP (B-type natriuretic peptide) and CST levels predicted the highest risk for both all-cause and cardiac deaths [HR = 5.18 (95% CI: 1.94–13.87, p = 0.001) and HR = 9.19 (95% CI: 2.75–30.78, p < 0.001), respectively]. Large-scale studies are needed to further assess the value of plasma CST in predicting heart failure prognosis. [ABSTRACT FROM AUTHOR]

Abnormal Ca2+ handling is a pivotal element of atrial fibrillation (AF) substrates. Catestatin (CST) modulates intracellular Ca2+ handling in cardiomyocytes (CMs). We investigated the effects of CST administration on atrial Ca2+ handling and AF susceptibility in rats with post-infarction heart failure (HF). Myocardial infarction (MI) was established by ligation of the left anterior descending coronary artery in rats. Two-week later, rats with post-infarction HF were randomly treated with saline (MI group) or CST (MI + CST group) for 4-week. Cellular Ca2+ imaging was performed by incubating atrial CMs with Fura-2 AM. An in vitro electrophysiological study was performed to assess the vulnerability to action potential duration (APD) alternans and AF. Ca2+ handling proteins expression was determined using western blotting. In atrial CMs, compared with the sham group, the sarcoplasmic reticulum (SR) Ca2+ load, Ca2+ transient (CaT) amplitude, and threshold for Ca2+ alternans were significantly decreased, but the diastolic intracellular Ca2+ level, SR Ca2+ leakage, and spontaneous Ca2+ events were markedly increased in the MI group. However, CST attenuated these Ca2+-handling abnormalities induced by post-infarction HF. Moreover, vulnerability to atrial APD alternans and AF was significantly increased in isolated hearts from the MI group compared to the sham group, whereas all effects were prevented by CST. CST treatment also preserved SR Ca2+-ATPase protein expression but decreased the protein levels of phosphorylated-ryanodine receptor 2 and phosphorylated-Ca2+/calmodulin-dependent protein kinase II in atria from post-infarction HF rats. Chronic CST treatment reduces AF vulnerability in rats with MI-induced HF by improving Ca2+ handling. • Chronic catestatin treatment can improve atrial Ca2+ handling in rats with myocardial infarction-induced heart failure. • Chronic catestatin treatment can reduce the vulnerability to atrial fibrillation in rats with post-infarction heart failure. • Catestatin may be a promising agent for preventing atrial fibrillation in post-infarction heart failure. [ABSTRACT FROM AUTHOR]

Highlights: [•] CST exerted antihypertensive and neuroprotective effects. [•] CST interacted with GABAergic systems and increased activities. [•] Akt and ERK signaling were involved in neuroprotective mechanisms. [•] CST+MUS may constitute new therapeutic agents for neurovascular disorders. [ABSTRACT FROM AUTHOR]

Abstract: Mucosal inflammation in patients with inflammatory bowel disease (IBD) is characterized by an alteration of prohormone chromogranin A (CgA) production. The recent demonstration of an implication of CgA in collagenous colitis and immune regulation provides a potential link between CgA-derived peptides (catestatin, CTS) and gut inflammation. Colitis was induced by administration of dextran sulfate sodium or 2, 4 dinitrobenzenesulfonic acid to C57BL/6 mice. Treatment with human (h)CTS or its proximal or distal part was started one day before colitis induction and colonic inflammatory markers were determined. Pro-inflammatory cytokines were evaluated in peritoneal isolated and bone marrow derived macrophages (BMDMs); p-STAT3 level was studied. Serum levels of CgA and CTS were assessed in experimental colitis and in a separate study in IBD patients and healthy controls. We show that sera from IBD patients and that in experimental colitis conditions the colonic level of mouse (m)CgA and mCTS are significantly increased. Moreover, in vivo treatment with human (h)CTS reduces the disease onset and suppresses exacerbated inflammatory responses in preclinical settings of colitis associated with an increase of p-STAT3. In vitro, hCTS treatment decreases proinflammatory cytokine release by peritoneal macrophages and BMDMs and increases p-STAT3 levels. These results support the hypothesis that CTS is increased during colitis and that hCTS modulates intestinal inflammation via the macrophage population and through a STAT-3 dependent pathway in a murine model of colitis. Identification of the molecular mechanism underlying the protective role of this peptide may lead to a novel therapeutic option in IBD. [Copyright &y& Elsevier]

Highlights: [•] The patients were grouped according to the quartile of CST concentration. [•] A correlation between CST and malignant arrhythmia in AMI patients is found. [•] Age, CST and NT-proBNP are independent predictors for MACE. [•] Increased blood glucose (≥6.1mmol/L) predicts malignant arrhythmia in AMI patients. [•] CST is a new predictor for prediction of malignant arrhythmia in patients with AMI. [Copyright &y& Elsevier]

Abstract: The aim of the study was to investigate the presence and distribution of the chromogranin A-derived peptide catestatin in the rat eye and trigeminal ganglion by immunofluorescence using an antibody which recognizes not only free catestatin but also larger fragments containing the sequence of catestatin. Western blots were performed in an attempt to characterize the immunoreactivities detected by the catestatin antiserum. Sparse immunoreactive nerve fibers were visualized in the corneal stroma, in the chamber angle, in the sphincter muscle but also in association with the dilator muscle, in the stroma of the ciliary body and processes, but dense in the irideal stroma, around blood vessels at the limbus and in the choroid and in cells of the innermost retina representing amacrine cells as identified by colocalization with substance P. Furthermore, catestatin-immunoreactivity was detected in the trigeminal ganglion in small to medium-sized cells and there were abundant catestatin-positive nerve fibers stained throughout the stroma of the ganglion. Double immunofluorescence of catestatin with substance P revealed colocalization both in cells of the trigeminal ganglion as well as in nerve fibers in the choroid. The immunoreactivities are present obviously as free catestatin and/or small-sized catestatin-containing fragments in the retina and ocular nerves but as large processed fragments as well, weak in the retina and more prominent in remaining ocular tissues, possibly in endothelial cells. This indicates that this peptide is a constituent of sensory neurons innervating the rat eye and the presence in amacrine cells in the retina is typical for neuropeptides. Catestatin is biologically highly active and might be of significance in the pathophysiology of the eye. [Copyright &y& Elsevier]

Abstract: The endogenous catecholamine release-inhibitory peptide catestatin (CST) regulates events leading to hypertension and cardiovascular disease. Earlier we studied the structure of CST by NMR, molecular modeling, and amino acid scanning mutagenesis. That structure has now been exploited for elucidation of interface pharmacophores that mediate binding of CST to its target, with consequent secretory inhibition. Designed pharmacophore models allowed screening of 3D structural domains. Selected compounds were tested on both cultured catecholaminergic cells and an in vivo model of hypertension; in each case, the candidates showed substantial mimicry of native CST actions, with preserved or enhanced potency and specificity. The approach and compounds have thus enabled rational design of novel drug candidates for treatment of hypertension or autonomic dysfunction. [Copyright &y& Elsevier]

Highlights: [•] Mixed expression of chromogranin A and α GABAAR subunits during hibernation. [•] High chromogranin A and α1 levels were typical of damaged neuron fields of torpor. [•] Low chromogranin A plus high α2,4 levels in few damaged neuron fields of arousal. [•] Perfusion of amygdala with catestatin caused inhibition of sympathetic outflow. [•] Distinct chromogranin A and α subunit expression rescue cardiovascular alterations. [ABSTRACT FROM AUTHOR]

Highlights: [•] Plasma CST levels in patients with moderate to severe heart failure were significantly elevated. [•] Heart failure patients with ischemic etiology had significantly higher plasma CST levels than those with non-ischemic heart disease. [•] Plasma CST was not an ideal marker in the diagnosis of moderate to severe HF. Combining CST and BNP did not provide incremental information in the diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: 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 Ca2+ 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 Ca2+ 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. [Copyright &y& Elsevier]

Abstract: Chromogranin A (CgA) and secretogranin II (SgII) of the granin family of uniquely acidic proteins secreted from elements of the diffuse neuroendocrine system are also produced by cells involved in inflammation. CgA and the CgA-derived peptides vasostatin-I and catestatin are products of polymorphonuclear neutrophils accumulating at sites of injury or infections while SgII and the Sg II-derived secretoneurin may contribute to neurogenic inflammation when released from sensory nerve terminals. This review is directed towards vasostatin-I, catestatin and secretoneurin as modulators of cells and tissues associated with inflammatory conditions. The accumulated literature indicates that concerted effects of vasostatin-I and catestatin may be relevant for the first-line host-defence against invading microorganisms, contrasting the apparent lack of antibacterial potencies in secretoneurin. Oppositely directed effects of vasostatin-I and secretoneurin on endothelial permeability and transendothelial extravasation are particularly striking. While vasostatin-I protects the integrity of the endothelial barrier against the disruptive effects of proinflammatory agents, secretoneurin activates transendothelial extravasation, chemotaxis and migration of leukocytes. Oppositely directed effects of vasostatin-I and secretoneurin on formation of blood vessels are also indicated, vasostatin-I inhibiting angiogenetic parameters while secretoneurin activates not only angiogenesis but also vascularization. [ABSTRACT FROM AUTHOR]

Abstract: In acute myocardial infarction increased plasma levels of chromogranin A are correlated with decreased survival. At the human chromogranin A gene locus there are two naturally occurring amino acid substitution variants within the catestatin region, i.e. Gly364Ser and Pro370Leu, displaying differential potencies towards inhibition of nicotinic cholinergic agonist-evoked catecholamine secretion from sympathochromaffin cells and different degrees of processing from the prohormone. Here, we examine whether two of the variants and the wild type catestatin may affect the development of infarct size during ischemic reperfusion in the Langendorff rat heart model. The hearts were subjected to regional ischemia followed by reperfusion in the presence or absence of synthetic variants of human catestatin. Compared to the Gly364Ser variant both the wild type and Pro370Leu variants increased infarct size while decreasing the cardiac levels of phosphorylated Akt and two of its downstream targets, FoxO1 and BAD. In conclusion, these findings suggest that, in contrast to the Gly364Ser variant, wild type catestatin and the Pro370Leu variant (allele frequency ~0.3%) increased myocardial infarct size via a mechanism involving dephosphorylation of Akt and the two downstream targets during ischemic reperfusion in the isolated rat heart. [ABSTRACT FROM AUTHOR]

Previous modeling (PDB 1cfk) of the catecholamine release-inhibitory “catestatin” region of chromogranin A (CgA) suggested a β-strand/loop/β-strand active conformation, displaying an electropositive Arg-rich loop (R351AR353GYGFR358). To explore this possibility, we studied NMR structures of linear and cyclic synthetic catestatin, bovine (bCgA344–364) or human (hCgA352–372). By 2-D 1H-NMR, the structure of linear catestatin (hCgA352–372) exhibited the NOE pattern of a coiled loop (PDB 1lv4). We then constrained the structure, cyclizing the putative Arg-rich loop connecting the β-strands: cyclic bCgA350–362 ([C0]F350RARGYGFRGPGL362[C+14]). Favored conformations of cyclic bCgA350–362 were determined by 1H-NMR and 13C-NMR spectroscopy. Cyclic bCgA350–362 conformers (PDB 1n2y) adopted a “twisted-loop” conformation. Alignment between the homology model and the cyclic NMR structure showed that, while portions of the NMR structure's mid-molecule and carboxy-terminus were congruent with the homology model (RMSD, 1.61–1.91 A˚), the amino-terminal “twisted loop” coiled inward and away from the model (RMSD, 3.36 A˚). Constrained cyclic bCgA350–362 did not exert nicotinic cholinergic antagonist activity (IC50>10 μM), when compared to full-length linear (IC50∼0.42–0.56 μM), or cyclic (IC50∼0.74 μM) catestatin. Thus, loss of activity in the small, constrained peptide did not result from either [Cys]-extension or cyclization, per se. While linear catestatin displays coiled character, a small cyclic derivative lost biological activity, perhaps because its amino-terminal domain deviated sharply from the predicted active conformation. These results refine the relationship between structure and function in catestatin, and suggest goals in future peptidomimetic syntheses, in particular attempts to constrain the correct amino-terminal shape for biological activity. [Copyright &y& Elsevier]

Chromogranin A (CgA) belongs to the family of chromogranin peptides which are contained in large dense-core vesicles. The novel CgA fragment catestatin (bovine CgA344–364; RSMRLSFRARGYGFRGPGLQL) is a potent inhibitor of catecholamine release by acting as a nicotinic cholinergic antagonist. Catestatin is a recently characterized neuropeptide, consisting of 21 amino acids, which might play an autocrine regulatory role in neuroendocrine secretion through its interaction with different nicotinic acetylcholine receptor subtypes. This study investigates for the first time the distribution of this peptide in the human auditory system using immunohistochemistry. A high density of catestatin-like immunoreactivity (catestatin-LI) is located in the spiral ganglion cells. In the dorsal cochlear nucleus, a high density of catestatin-LI consists of varicose fibers, immunoreactive varicosities and immunoreactive neurons. A moderate density is detected in the ventral cochlear and the medial vestibular nucleus. A low density is found in the inferior colliculus and superior olivary complex. The study indicates that catestatin is distinctly distributed in the auditory system, suggesting a role as a neuromodulatory peptide. Further studies should elucidate a possible interaction with other neurotransmitters in the auditory system. [Copyright &y& Elsevier]

• Obesity, insulin resistance, and hypertension are known as being the main risk factors for metabolic syndrome (MetS). • MetS is involve to the progression of other pathologies like T2DM, atherosclerotic cardiovascular disease, and NAFLD. • Catestatin is bioactive peptide with 21 amino acids, derived through cleaving of chromogranin A (CHGA/CgA). • CST is responsible for insulin sensitivity improvement, hypertension reduction and obesity attenuation. 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. [ABSTRACT FROM AUTHOR]

• Catestatin (CST) preserves infarcted myocardium in ischemia reperfusion (I/R). • One main protection of CST is via salvage of oxidative-stress induced apoptosis. • Novel mechanisms of activation of β2 receptor and PI3K/Akt signaling involves. Apoptosis induced by oxidative stress is one of the most important cardiomyocytes losses during ischemia-reperfusion (I/R). Catestatin (CST) has been demonstrated to have the anti-oxidative capacity in vitro. We hypothesized that CST intervention could reduce apoptosis of cardiomyocytes induced by oxidative stress in I/R. In Langendorff-perfused rat heart global I/R model, CST was introduced at the reperfusion stage. In comparison to the control group, CST led to preservation on activities of superoxide dismutase and glutathione peroxidase, improvement of hemodynamics, and reduced infarction area in reperfused myocardium. The protection of CST was also shown by less apoptotic cardiomyocytes in TUNEL staining, less caspase-3 activation, and increased phosphorylation of protein kinase B (PKB/Akt) in Western blot. To further demonstrate the benefits of CST and explore the possible underlying mechanism, H 2 O 2 -challenged primary-cultured neonatal rat cardiomyocytes were used to simulate the oxidative-stressed scenario. CST incubation with the H 2 O 2 -challenged cardiomyocytes led to reduction of apoptosis, which was demonstrated by less Hoechst 33342 positive staining of nuclei, less caspase-3 activation, and DNA fragmentation. The effect of CST was abrogated by pretreatment of the cardiomyocytes with the PI3K inhibitor LY294002. Furthermore, Akt activation and the anti-apoptosis effect of CST were abolished by pretreatment of the cardiomyocytes with β2 receptor inhibitor ICI118551. Thus, the salvage of oxidative-stress-induced apoptotic cardiomyocytes in I/R by CST might involve activation β2 receptor and regulation of PI3K/Akt signaling in reperfusion injury salvage kinase (RISK) pathway. [ABSTRACT FROM AUTHOR]