gastrins and Myocardial-Infarction

Acute myocardial infarction (MI) is one of the leading causes of death in humans. Our previous studies showed that gastrin alleviated acute myocardial ischaemia-reperfusion injury. We hypothesize that gastrin might protect against heart injury after MI by promoting angiogenesis. An MI model was simulated by ligating the anterior descending coronary artery in adult male C57BL/6J mice. Gastrin was administered twice daily by intraperitoneal injection for 2 weeks after MI. We found that gastrin reduced mortality, improved myocardial function with reduced infarct size and promoted angiogenesis. Gastrin increased HIF-1α and VEGF expression. Downregulation of HIF-1α expression by siRNA reduced the proliferation, migration and tube formation of human umbilical vein endothelial cells. These results indicate that gastrin restores cardiac function after MI by promoting angiogenesis via the HIF-1α/VEGF pathway.

Topics: Animals; Cell Proliferation; Gastrins; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Neovascularization, Pathologic; Signal Transduction; Vascular Endothelial Growth Factor A

It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown.. Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 μg/Kg body weight/day, 100 μL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis.. We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK. Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.

Topics: Animals; Apoptosis; Biomarkers; Cardiotonic Agents; Disease Management; Disease Models, Animal; Disease Susceptibility; Echocardiography; Echocardiography, Three-Dimensional; Gastrins; Heart Function Tests; Immunohistochemistry; Male; Mice; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Vascular Endothelial Growth Factor A

Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI.. Adult male Sprague-Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff-perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal-regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin-mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin-mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes.. These results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.

Topics: Aged; Angina, Unstable; Animals; Apoptosis; Female; Gastrins; Heart; Hormones; Humans; Isolated Heart Preparation; Male; MAP Kinase Signaling System; Middle Aged; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Percutaneous Coronary Intervention; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Receptor, Cholecystokinin B; Signal Transduction; STAT3 Transcription Factor; Troponin I

We determined gastrin and pepsinogen I in serum samples obtained in 1968-69 from 256 women (175 women 54 years old and 81 women 60 years old when sampled). The concentration of gastrin in serum was significantly (p less than 0.01) and positively correlated with the incidence of myocardial infarction during a 12-year follow-up, with age taken into account as a background variable in multivariate analysis. It was not correlated with overall mortality or with the 12-year incidences of angina pectoris, electrocardiographic changes indicating ischemic heart disease, or stroke. The correlation with myocardial infarction was independent of smoking, systolic blood pressure, indices of obesity, concentrations of blood glucose during fasting and of serum triglycerides and cholesterol, and of the presence of diabetes mellitus at screening or during follow-up. Serum gastrin was significantly (p less than 0.05) related to body mass index (positive age-specific relation) and to smoking (negative age-specific relation). These findings may provide a new aspect to analysis of risk factors for myocardial infarction.

Topics: Adult; Cardiovascular Diseases; Female; Gastrins; Humans; Longitudinal Studies; Middle Aged; Myocardial Infarction; Pepsinogens; Risk; Smoking; Sweden

Measurements of plasma pancreatic polypeptide and gastrin are reported for the first time in patients with acute myocardial infarction and compared with clinical signs of vagal or sympathetic overactivity. Pancreatic polypeptide concentrations were assessed as an index of vagal activity, but elevated values of pancreatic polypeptide found in 7 of the 13 patients on admission did not correlate with clinical evidence of vagal overactivity. The mean pancreatic polypeptide concentrations were not higher in patients with clinical vagal overactivity than in patients with clinical sympathetic overactivity during the 12 h after the onset of symptoms of acute myocardial infarction. Mean gastrin levels were significantly higher on admission and at 4, 5, 6 and 8 h after the onset of infarction in the patients with clinical features of sympathetic overactivity than in the patients with clinical vagal overactivity. Thus plasma gastrin warrants further assessment as an index of sympathetic overactivity in acute myocardial infarction.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Autonomic Nervous System; Fatty Acids, Nonesterified; Gastrins; Humans; Male; Middle Aged; Myocardial Infarction; Pancreatic Polypeptide; Sympathetic Nervous System; Vagus Nerve

In order to further investigate hormonal changes and possible metabolic consequences in acute pancreatitis, 10 cases with a mild form of the disease was studied. The influence of tissue injury per se on the hormones in question was assessed from comparison with the hormone levels in the course of myocardial infarction (MI) in 9 cases. Insulin and glucose showed no consistent changes. Glucagon was suppressed on admission, 22 +/- 10 pg . ml-1, compared with the ultimate concentration, 40 +/- 20 pg . ml-1 (p less than 0.05), and with the initial value in MI, 74 +/- 32 pg . ml-1 (p less than 0.01). Serum calcitonin (CT) was strongly elevated initially, 348 +/- 313 pg . ml-1, compared with the ultimate level, 24 +/- 7 pg . ml-1 (p less than 0.001), and with the normal initial level in MI, 43 +/- 44 pg . ml-1 (p less than 0.01). Serum CT elevations were time-related to a slight reduction in corrected serum Ca, which might reflect a biological expression of this substance. In pancreatitis, parathyroid hormone (PTH) remained normal and unchanged throughout the study, whereas patients with MI had an increased level of this hormone on admission, 0.19 +/- 0.08 microgramEq . 1(-1), compared with the ultimate concentration, 0.09 +/- 0.03 microgram/q . 1(-1) (p less than 0.02) and with the initial concentration in pancreatitis, 0.11 +/- 0.06 microgramEq . 1(-1) (p less than 0.05). Supranormal PTH levels were found in more than half of the infarction patients on days 0 and 1.

Topics: Acute Disease; Adult; Aged; Calcitonin; Calcium; Female; Gastrins; Glucagon; Hormones; Humans; Insulin; Male; Middle Aged; Myocardial Infarction; Pancreatitis; Parathyroid Hormone

A significant rise in immunoreactive gastrin in a proportion of patients with rheumatoid arthritis is confirmed. Such a rise does not seem to occur in other inflammatory or tissue destructive diseases. The patients with raised immunoreactive gastrin appear to form a separate population but the factors determining this separation remain obscure. Anti-inflammatory drugs, at least during short-term administration have no influence on immunoreactive gastrin concentrations.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antigens; Arthritis; Arthritis, Rheumatoid; Female; Gastrins; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Myocardial Infarction; Osteoarthritis; Psoriasis; Radioimmunoassay; Spondylitis, Ankylosing; Tuberculosis, Pulmonary