The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease.

Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic ß-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.

Eyelid basal cell carcinoma with neuroendocrine differentiation: a case report and literature review.

Basal cell carcinoma (BCC) is the most common type of malignant tumor in the periocular region. BCCs with neuroendocrine differentiation in the periocular region, however, have not been described in the literature.We present a retrospective case review of a patient with an eyelid BCC with neuroendocrine differentiation. Demographical, clinical, radiological, surgical, histological, and follow-up data are presented.The patient presented with a slow-growing lesion of the eyelid with associated epiphora and dull ache. Initial incisional biopsy of the lesion revealed an infiltrating carcinoma composed of epithelial cells. Immunohistochemistry showed that the tumor was positive for p40, Ber-Ep4, neuron specific enolase (NSE), chromogranin A, CD56 (NCAM), and synaptophysin. The pathology from the margin-controlled excision showed basosquamous cell carcinoma with neuroendocrine differentiation. Tumor recurrence was not detected clinically at the post-operative six-month review.BCC with neuroendocrine marker positivity represents an important diagnostic differential for rare eyelid carcinomas such as primary cutaneous neuroendocrine carcinoma and metastatic small cell carcinoma that have a poor prognosis. The prognostic importance of neuroendocrine marker positivity in BCCs is uncertain. The present case provides further evidence for neuroendocrine differentiation in BCCs.

[The observation of secretogranin â ¢ in the peripheral blood and vitreous of patients with diabetic retinopathy].

Objective: To study the expression levels of secretogranin Ⅲ (SCG3) in the peripheral blood and vitreous of patients with diabetic retinopathy (DR). Methods: Cross-sectional research. A total of 77 patients (41 men and 36 women, 77 eyes) received vitrectomy in Tianjin Medical University Eye Hospital from May to December 2018, with an average age of (60.75±11.34) years. According to the blood glucose level, diabetes history and fundus status, all the patients were divided into the DR group and the non-diabetic group. According to the patients' blood lipids and body mass index (BMI), patients were further divided into subgroups of high blood lipids, normal blood lipids, high BMI and normal BMI. All patients were tested with eye examinations, height and weight to calculate the BMI, and blood lipid levels in the peripheral blood. The vitreous was collected during the vitrectomy surgery, and the levels of SCG3 in the vitreous and peripheral blood were analyzed by ELISA. All the data were analyzed statistically with Wilcoxon rank sum test. Results: There were 43 patients in the DR group, among whom 25 had hyperlipidemia, 18 had normal blood lipids, 22 had a high BMI, and 21 had a normal BMI. There were 34 patients in the non-diabetic group, among whom 13 had hyperlipidemia, 21 had normal blood lipids, 17 had a high BMI, and 17 had a normal BMI. The level of SCG3 in the DR group [6.02 (4.34, 11.76) ng/ml] was higher than that in the non-diabetic group [4.30 (3.20, 10.78) ng/ml] (Z=-2.339, P =0.019). The level of SCG3 in the hyperlipidemia subgroup of the DR patients [7.94 (5.33, 13.51) ng/ml] was higher than that in the normal blood lipid subgroup of the non-diabetic patients [4.04 (3.12, 7.77) ng/ml] (Z=-3.473, P=0.001), and higher than that in the DR patients without hyperlipidemia [4.45 (3.71, 9.14) ng/ml] (Z=-2.511, P=0.012). The level of SCG3 in the DR patients with a high BMI [7.12 (4.56, 13.12) ng/ml] was higher than that in the non-diabetic patients with a normal BMI [3.53 (3.16, 4.38) ng/ml] (Z=-3.767, P =0.000). The level of SCG3 in the DR patients with a normal BMI [5.72 (4.10, 11.60) ng/ml] was higher than that in the non-diabetic patients with a normal BMI (Z=-2.862, P = 0.004). SCG3 in the plasma was rare or can not be detected. Conclusions: The concentration of SCG3 in the vitreous increase in DR patients. However, SCG3 can not be detected in the healthy vascular system. (Chin J Ophthalmol, 2020, 56: 933-937).

What is the appropriate management of nonfunctioning pancreatic neuroendocrine tumours disclosed on screening in adult patients with multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterised by a predisposition to the development of endocrine tumours of the parathyroid glands, pituitary and pancreas: 30%-80% of patients with MEN1 develop pancreatic neuroendocrine tumours (pNETs), with metastatic tumours and/or their sequelae contributing to increased morbidity and early mortality. The optimal management of nonfunctioning (NF) pNETs in MEN1 remains controversial. Whilst pancreatic resection is widely recommended for tumours >2 cm, for smaller tumours (≤2 cm) a well-established consensus guiding the indications for surgical intervention does not exist. Although total pancreatectomy may be curative for some patients, both short- and long-term complications make this an unsatisfactory option for many patients. For small (<2 cm) MEN1 NF-pNETs, some clinicians advocate surveillance based largely on retrospective data that suggest 50%-80% of these lesions are stable over time and infrequently exhibit accelerated growth rates. It is increasingly recognised, however, that NF-pNETs exhibit unpredictable malignant behaviour that is not determined by tumour size alone, thereby prompting other clinicians to advocate surgery for all MEN1 NF-pNETs, irrespective of size. Such uncertainty poses clinical management challenges with regards to the timing and extent of surgery, which is further hindered by the inability to stratify patients based on predicted tumour behaviour. It is therefore critical that future MEN1 research initiatives include: (a) the discovery of biomarkers that better predict tumour behaviour; (b) the evaluation of medical therapies that may delay, or even prevent, the need for pancreatic surgery; and, ultimately, (c) improvement in the quality of life for individuals with MEN1. Here, based on the published literature, we address the Clinical Question, 'What is the management of NF-pNETs disclosed on screening in adult patients with MEN1?'.

[Neuroendocrine neoplasms : Two families with distinct features unified in one classification (German version)]. / Neuroendokrine Neoplasien : Zwei Familien mit sehr unterschiedlichen Charakteristika vereint in einer Klassifikation.

All neuroendocrine neoplasms (NENs) are characterized by the expression of synaptophysin and chromogranin A (or B). Yet, they are not a homogeneous group of tumors. Paradigmatic for these tumors are the NENs of the gastroenteropancreatic (GEP) system. Two NEN families can be distinguished: predominantly well differentiated and low-proliferative NENs, called neuroendocrine tumors (NET), and poorly differentiated and high-proliferative NENs, called neuroendocrine carcinomas (NECs). Based on their proliferative activity, GEP NETs are further classified into G1, G2, and G3 tumors. NECs are per definition G3 carcinomas. The morphological NEN dichotomy is supported by differences in epidemiology, genetics, clinics, and prognosis, and potentially has its cause originating from different progenitor cells. Genetically, NECs are distinguished by TP53 and RB1 alterations, which are lacking in NETs and are helpful in the distinction of NETs from NECs. Comparison of the GEP NEN WHO classification with extragastroenteropancreatic NEN classifications commonly reveal differences in terminology and categorization. In addition, they lack a grading system. However, common to all NEN classifications is the recognition of two tumor families differing in histological differentiation and prognosis. This allows the construction of a uniform classification frame for all NENs.

How intravesicular composition affects exocytosis.

Large dense core vesicles and chromaffin granules accumulate solutes at large concentrations (for instance, catecholamines, 0.5-1 M; ATP, 120-300 mM; or Ca2+, 40 mM (12)). Solutes seem to aggregate to a condensed protein matrix, which is mainly composed of chromogranins, to elude osmotic lysis. This association is also responsible for the delayed release of catecholamines during exocytosis. Here, we compile experimental evidence, obtained since the inception of single-cell amperometry, demonstrating how the alteration of intravesicular composition promotes changes in the quantum characteristics of exocytosis. As chromaffin cells are large and their vesicles contain a high concentration of electrochemically detectable species, most experimental data comes from this cell model.

[Physiological, pathophysiological and clinical significance of chromogranins/secretogranins]. / A kromograninok, szekretograninok élettani, kórélettani és klinikai szerepérol.

This paper investigates the fundamental knowledge, build-up, as well as essential structural and important features of the big family of chromogranins/secretogranins. Previously the different properties and the slightly diverging funcional relations of the two family members were in focus. Later on, it has been discovered that they are essentially two similar compounds with identical structures and functions, and they are chemically, biochemically related. From details discovered so far we can tell that they are long polypeptid chains formed from amino acids. Based on insights gained until now we can also state that these compounds are formed in Ca++ containing environments with acidic pH. Among the compounds there are several molecules which have characteristic oligosacharid groups. This is especially interesting because oligosacharid chains with sialic acid in terminal position play an important role in the recognising and connectional processes. The chromogranins/secretogranins are mostly formed in neuroendocrine cells, but are also capable of building up in any cell type in the organism during pathological processes. Intracellular biogenesis takes place in the dense endoplasmatic reticulum across the mitochondrium, developing biogenetic granulums, followed by the stimulus-motivated secretum (exocytosis). The next stage of the molecular development is the specific break-up of the long polypeptid chains into shorter fragments. These fragments have individual effects. Some important clinical (diagnostic, prognostic) significance and connections are also touched upon in this paper, however, the cardiovascular, immunological systems and the tumors are mostly in focus. There are more immunological, cardiovascular and tumoral data. It is stated that as these molecules are in close connection with all of the organisms and systems of the body, a new chief organisator system has been identified. This chief organisator is closely connected with the central nervous system. Orv Hetil. 2017; 158(28): 1092-1099.

The intravesicular cocktail and its role in the regulation of exocytosis.

The accumulation of neurotransmitters within secretory vesicles (SVs) far exceeds the theoretical tonic concentrations in the cytosol, a phenomenon that has captivated the attention of scientists for decades. For instance, chromaffin granules can accumulate close to molar concentrations of catecholamines, along with many other products like ATP, calcium, peptides, chromogranins, ascorbate, and other nucleotides. In this short review, we will summarize the interactions that are currently believed to occur between the elements that make up the vesicular cocktail in the acidic environment of SVs, and how they permit the accumulation of such high concentrations of certain components. In addition, we will examine how the vesicular cocktail regulates the exocytosis of neurotransmitters. In this review, we have highlighted the mechanisms that permit the storage of neurotransmitters and hormones inside secretory vesicles. We also have proposed a novel model based in the intravesicular interactions of the main components of this inner cocktail - catecholamines, ATP, and chromogranins - to allow the accumulation of near molar concentrations of transmitters in secretory vesicles. This article is part of a mini review series on Chromaffin cells (ISCCB Meeting, 2015).

Malignant cell-derived extracellular vesicles express different chromogranin epitopes compared to prostasomes.

BACKGROUND: Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS: We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS: A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION: Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers.

The NO stimulator, Catestatin, improves the Frank-Starling response in normotensive and hypertensive rat hearts.

The myocardial response to mechanical stretch (Frank-Starling law) is an important physiological cardiac determinant. Modulated by many endogenous substances, it is impaired in the presence of cardiovascular pathologies and during senescence. Catestatin (CST:hCgA352-372), a 21-amino-acid derivate of Chromogranin A (CgA), displays hypotensive/vasodilatory properties and counteracts excessive systemic and/or intra-cardiac excitatory stimuli (e.g., catecholamines and endothelin-1). CST, produced also by the myocardium, affects the heart by modulating inotropy, lusitropy and the coronary tone through a Nitric Oxide (NO)-dependent mechanism. This study evaluated the putative influence elicited by CST on the Frank-Starling response of normotensive Wistar-Kyoto (WKY) and hypertensive (SHR) hearts by using isolated and Langendorff perfused cardiac preparations. Functional changes were evaluated on aged (18-month-old) WKY rats and SHR which mimic human chronic heart failure (HF). Comparison to WKY rats, SHR showed a reduced Frank-Starling response. In both rat strains, CST administration improved myocardial mechanical response to increased end-diastolic pressures. This effect was mediated by EE/IP3K/NOS/NO/cGMP/PKG, as revealed by specific inhibitors. CST-dependent positive Frank-Starling response is paralleled by an increment in protein S-Nitrosylation. Our data suggested CST as a NO-dependent physiological modulator of the stretch-induced intrinsic regulation of the heart. This may be of particular importance in the aged hypertrophic heart, whose function is impaired because of a reduced systolic performance accompanied by delayed relaxation and increased diastolic stiffness.

Vasostatins: new molecular targets for atherosclerosis, post-ischaemic angiogenesis, and arteriogenesis.

The chromogranin-secretogranin secretory proteins-granins-are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage.

Vasostatin-1 restores autistic disorders in an idiopathic autism model (BTBR T+ Itpr3tf/J mice) by decreasing hippocampal neuroinflammation.

Chromogranin A (CgA), a âˆ¼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA250-301), Vasostatin 1 (VS1: hCgA1-76), and catestatin (CST: CgA 352-372). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.

Reduced expression of secretogranin VGF in laryngeal squamous cell carcinoma.

Laryngeal cancer accounts for one-third of all head and neck tumors, with squamous cell carcinoma (SCC) being the most predominant type, followed by neuroendocrine tumors. Chromogranins, are commonly used as biomarkers for neuroendocrine tumors, including laryngeal cancer. It has been reported that secretogranin VGF, a member of the chromogranin family, can be also used as a significant biomarker for neuroendocrine tumors. However, the expression and role of VGF in laryngeal carcinomas have not been previously investigated. Therefore, the present study aimed to determine the expression levels of VGF in laryngeal SCC (LSCC). The present study collected tumor tissues, as well as serum samples, from a cohort of 15 patients with LSCC. The results of reverse transcription-quantitative PCR, western blot analysis and immunofluorescence assays showed that the selective VGF precursor was downregulated in patients with LSCC. Notably, in tumor tissue, the immunoreactivity for VGF was found in vimentin-positive cells, probably corresponding to T lymphocytes. The current preliminary study suggested that the reduced expression levels of VGF observed in tumor tissue and at the systemic level could sustain LSCC phenotype. Overall, VGF could be a potential biomarker for detecting neoplastic lesions with a higher risk of tumor invasiveness, even in non-neuroendocrine tumors.

The antimicrobial peptides secreted by the chromaffin cells of the adrenal medulla link the neuroendocrine and immune systems: From basic to clinical studies.

The increasing resistance to antibiotic treatments highlights the need for the development of new antimicrobial agents. Antimicrobial peptides (AMPs) have been studied to be used in clinical settings for the treatment of infections. Endogenous AMPs represent the first line defense of the innate immune system against pathogens; they also positively interfere with infection-associated inflammation. Interestingly, AMPs influence numerous biological processes, such as the regulation of the microbiota, wound healing, the induction of adaptive immunity, the regulation of inflammation, and finally express anti-cancer and cytotoxic properties. Numerous peptides identified in chromaffin secretory granules from the adrenal medulla possess antimicrobial activity: they are released by chromaffin cells during stress situations by exocytosis via the activation of the hypothalamo-pituitary axis. The objective of the present review is to develop complete informations including (i) the biological characteristics of the AMPs produced after the natural processing of chromogranins A and B, proenkephalin-A and free ubiquitin, (ii) the design of innovative materials and (iii) the involvement of these AMPs in human diseases. Some peptides are elective biomarkers for critical care medicine, may play an important role in the protection of infections (alone, or in combination with others or antibiotics), in the prevention of nosocomial infections, in the regulation of intestinal mucosal dynamics and of inflammation. They could play an important role for medical implant functionalization, such as catheters, tracheal tubes or oral surgical devices, in order to prevent infections after implantation and to promote the healing of tissues.

Assessment of stress response attenuation with caudal morphine using a surrogate marker during pediatric cardiac surgery.

BACKGROUND: Measurement of biomarkers representing sympathetic tone and the surgical stress response are helpful for objective comparison of anesthetic protocols. AIMS: The primary aim was to compare changes in chromogranin A levels following pump pediatric cardiac surgery between children who received bolus caudal morphine and those who received a conventional intravenous narcotic-based anesthesia regime. The secondary objectives were to compare hemodynamic responses to skin incision and the magnitude of the rise in blood sugar values between the groups. SETTINGS AND DESIGN: A prospective observational study at a tertiary cardiac center. MEASUREMENTS AND METHODS: Sixty pediatric cardiac surgical patients were randomized to Group I [n= 30] to receive intravenous narcotic-based anesthesia and Group II [n = 30] to receive single-shot caudal morphine. Baseline and postoperative chromogranin A levels, the hemodynamic response to skin incision, changes in blood sugar levels, and the total intravenous narcotic dose administered were recorded for each participant. STATISTICAL ANALYSIS: Pearson's Chi-squared test was used for comparison of categorized variables, and Mann-Whitney test was used for the analysis of continuous data. RESULTS: Changes in chromogranin A levels and blood sugar levels were comparable in both groups. Group II received a lower narcotic dosage (P ≤ 0.001), and the response to skin incision as reflected by systolic pressure rise was less (P = 0.006). CONCLUSIONS: Surgical stress response attenuation was similar to caudal morphine as compared with intravenous narcotic-based anesthesia techniques as reflected by a similar increase in chromogranin A levels.

Serum levels of chromogranins and secretogranins correlate with the progress and severity of Parkinson's disease.

Little is known about the relevance of chromogranins (Cgs) and secretogranins (Sgs) in Parkinson's disease (PD). In this study, we determined serum levels of CgA, CgB, and SgII in PD patients and assessed their association with disease severity. PD patients were recruited, identified, and classified as having early (n = 14), intermediate (n = 18), or late (n = 4) stage disease according to Hoehn-Yahr scores. The serum concentrations of CgA, CgB, and SgII in patients with well-defined PD (n = 36) and in healthy controls (n = 52) were measured by enzyme-linked immunosorbent assay. Compared with controls, serum CgA levels were significantly elevated and serum SgII levels were significantly reduced in PD patients (both P < 0.05). There was no difference in serum CgB levels between the two groups. Both serum CgA and SgII levels changed progressively over time from early to intermediate to late stage (P < 0.05). Spearman correlation analysis revealed that serum CgA and SgII levels correlated with Hoehn-Yahr and UPDRS scores (P < 0.001). These results indicate that changes in serum levels of CgA and SgII may be closely related to the severity of PD.

Chromogranin-A and its derived peptides and their pharmacological effects during intestinal inflammation.

The gastrointestinal tract is the largest endocrine organ that produces a broad range of active peptides. Mucosal changes during inflammation alter the distribution and products of enteroendocrine cells (EECs) that play a role in immune activation and regulation of gut homeostasis by mediating communication between the nervous, endocrine and immune systems. Patients with inflammatory bowel disease (IBD) typically have altered expression of chromogranin (CHG)-A (CHGA), a major soluble protein secreted by EECs that functions as a pro-hormone. CHGA gives rise to several bioactive peptides that have direct or indirect effects on intestinal inflammation. In IBD, CHGA and its derived peptides are correlated with the disease activity. In this review we describe the potential immunomodulatory roles of CHGA and its derived peptides and their clinical relevance during the progression of intestinal inflammation. Targeting CHGA and its derived peptides could be of benefit for the diagnosis and clinical management of IBD patients.

Chromofungin, CgA47-66-derived peptide, produces basal cardiac effects and postconditioning cardioprotective action during ischemia/reperfusion injury.

Endogenous chromogranin A (CgA)-derived peptides are secreted by nervous, endocrine and immune cells. Chromofungin (Chr: CgA47-66) is one of these peptides that display antimicrobial activities and activate neutrophils, with important implications in inflammation and innate immunity. The aim of the present study is to examine the effects of Chr on isolated and Langendorff perfused rat hearts. The study was performed by using the isolated and Langendorff perfused rat hearts, Elisa assay and real-time PCR. We found that, under basal conditions, increasing doses (11-165nM) of Chr induced negative inotropic effects without changing coronary pressure. This action was mediated by the AKT/eNOS/cGMP/PKG pathway. We also found that Chr acted as a postconditioning (PostC) agent against ischemia/reperfusion (I/R) damages, reducing infarct size and LDH level. Cardioprotection involved PI3K, RISK pathway, MitoKATP and miRNA-21. We suggest that Chr directly affects heart performance, protects against I/R myocardial injuries through the activation of prosurvival kinases. Results may propose Chr as a new physiological neuroendocrine modulator able to prevent heart dysfunctions, also encouraging the clarification of its clinical potential.