calpain and Coronary-Artery-Disease

Despite many advances in percutaneous and surgical interventions in the treatment of coronary artery disease (CAD), up to one-third of patients are still either not candidates or receive suboptimal revascularization. Calpains are a class of calcium-activated non-lysosomal cysteine proteases that serve as a proteolytic unit for cellular homeostasis. Uncontrolled activation of calpain has been found to be involved in the pathogenesis of myocardial reperfusion injury, cardiac hypertrophy, myocardial stunning and cardiac ischemia. Inhibition of calpains has been shown to significantly attenuate myocardial stunning and reduced infarct size after ischemia-reperfusion. Calpain inhibition therefore serves as a potential medical therapy for patients suffering from a number of diseases, including CAD.

Topics: Animals; Calpain; Cardiomegaly; Coronary Artery Disease; Enzyme Activation; Humans; Myocardial Reperfusion Injury

Diabetes mellitus is one of the most common endocrine disorders. It affects almost 6% of the world's population, and its prevalence continues to increase. The causes of diabetes mellitus are multifactorial, and in the general population both genetic and environmental factors contribute evenly to its development. Several genes have been consistently associated with type 2 diabetes mellitus; however, it is not clear how many of those translate into increased cardiovascular disease risk. Recent evidence suggests that genetic variation at the CALPN10, FABP4, GK, GST, PPARA, and PPARG loci may confer higher cardiovascular disease risk in patients with type 2 diabetes mellitus. However, the evidence is scattered and inconclusive and its translation into practical clinical testing will require studies properly designed to examine not only simple genetic associations but also gene-gene and gene-environment interactions.

Topics: Adipose Tissue; Calpain; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Progression; Fatty Acid-Binding Proteins; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glutathione Transferase; Humans; Oxidative Stress; Polymorphism, Genetic; PPAR gamma; Smoking

Calpain activation during ischemia is known to play critical roles in myocardial remodeling. We hypothesize that calpain inhibition (CI) may serve to reverse and/or prevent fibrosis in chronically ischemic myocardium.. Yorkshire swine were fed a high-cholesterol diet for 4 weeks followed by placement of an ameroid constrictor on the left circumflex artery to induce myocardial ischemia. 3 weeks later, animals received either: no drug; high-cholesterol control group (CON; n = 8); low-dose CI (0.12 mg/kg; LCI, n = 9); or high-dose CI (0.25 mg/kg; HCI, n = 8). The high-cholesterol diet and CI were continued for 5 weeks, after which myocardial tissue was harvested. Tissue samples were analyzed by western blot for changes in protein content.. In the setting of hypercholesterolemia and chronic myocardial ischemia, CI decreased the expression of collagen in ischemic and nonischemic myocardial tissue. This reduced collagen content was associated with a corresponding decrease in Jak/STAT/MCP-1 signaling pathway, suggesting a role for Jak 2 signaling in calpain activity. CI also decreases the expression of focal adhesion proteins (vinculin) and stabilizes the expression of cytoskeletal and structural proteins (N-cadherin, α-fodrin, desmin, vimentin, filamin, troponin-I). CI had no significant effect on metabolic and hemodynamic parameters.. Calpain inhibition may be a beneficial medical therapy to decrease collagen formation in patients with coronary artery disease and associated comorbidities.

Topics: Animals; Calpain; Chemokine CCL2; Collagen; Coronary Artery Disease; Disease Models, Animal; Fibrosis; Glycoproteins; Hypercholesterolemia; Janus Kinase 2; Myocardial Ischemia; Myocardium; Signal Transduction; STAT Transcription Factors; Swine; Ventricular Remodeling

Topics: Animals; Calpain; Coronary Artery Disease; Drug Discovery; Fibrosis; Glycoproteins; Hypercholesterolemia; Myocardial Ischemia; Myocardium; Swine; Ventricular Remodeling

Apoptosis is a key feature of advanced atherosclerotic plaques. Attraction signals such as p43 released from apoptotic cells play a crucial role in the timely removal of the apoptotic remnants by recruiting fresh phagocytes. Here, we sought to determine whether p43 may link apoptosis to inflammation and plaque progression.. RT-PCR and immunohistochemistry showed that p43 was abundantly expressed in human plaques compared with nonatherosclerotic mammary arteries and colocalized with splicing factor SC-35. Cell culture experiments indicated that p43 expression was associated with enhanced protein translation. On initiation of apoptosis or necrosis, p43 was cleaved by calpains and released as truncated protein p43(apoptosis-released factor [ARF]). Processing of p43 into endothelial monocyte activating polypeptide II was not observed. Full-length p43, but not p43(ARF) or endothelial monocyte activating polypeptide II, activated THP1 monocytes (upregulation of tumor necrosis factor alpha, interleukin 1 beta, interleukin 8, macrophage inflammatory protein (MIP)-1 alpha, MIP1 beta, MIP2 alpha) and endothelial cells (enhanced synthesis of E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tissue factor). The chemotactic activity of p43 or fragments thereof was poor compared with ATP. Treatment of smooth muscle cells with p43 did not induce cell death.. p43 is cleaved during apoptosis by calpains and released as a truncated protein that is harmless for the structure of the plaque.

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Calpain; Carotid Artery Diseases; Case-Control Studies; Cells, Cultured; Coronary Artery Disease; Cytokines; Disease Models, Animal; Disease Progression; Endothelial Cells; Female; Humans; Immunohistochemistry; Inflammation; Inflammation Mediators; Male; Mice; Mice, Knockout; Monocytes; Myocytes, Smooth Muscle; Neoplasm Proteins; Nuclear Proteins; Protein Biosynthesis; Protein Processing, Post-Translational; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoproteins; RNA-Binding Proteins; RNA, Messenger; Serine-Arginine Splicing Factors; Time Factors; Transfection; Up-Regulation