title: Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications.
abstract: Cardiovascular disease is the leading cause of death in the U.S. and other developed countries. Metabolic syndrome, including obesity, diabetes/insulin resistance, hypertension and dyslipidemia is a major threat for public health in the modern society. It is well established that metabolic syndrome contributes to the development of cardiovascular disease collective called as cardiometabolic disease. Despite documented studies in the research field of cardiometabolic disease, the underlying mechanisms are far from clear. Proteases are enzymes that break down proteins, many of which have been implicated in various diseases including cardiac disease. Matrix metalloproteinase (MMP), calpain, cathepsin and caspase are among the major proteases involved in cardiac remodeling. Recent studies have also implicated proteases in the pathogenesis of cardiometabolic disease. Elevated expression and activities of proteases in atherosclerosis, coronary heart disease, obesity/insulin-associated heart disease as well as hypertensive heart disease have been documented. Furthermore, transgenic animals that are deficient in or over-express proteases allow scientists to understand the causal relationship between proteases and cardiometabolic disease. Mechanistically, MMPs and cathepsins exert their effect on cardiometabolic diseases mainly through modifying the extracellular matrix. However, MMP and cathepsin are also reported to affect intracellular proteins, by which they contribute to the development of cardiometabolic diseases. On the other hand, activation of calpain and caspases has been shown to influence intracellular signaling cascade including the NF-κB and apoptosis pathways. Clinically, proteases are reported to function as biomarkers of cardiometabolic diseases. More importantly, the inhibitors of proteases are credited with beneficial cardiometabolic profile, although the exact molecular mechanisms underlying these salutary effects are still under investigation. A better understanding of the role of MMPs, cathepsins, calpains and caspases in cardiometabolic diseases process may yield novel therapeutic targets for treating or controlling these diseases. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, School of Pharmacy, College of Health Sciences, Laramie, WY 82071, USA. Electronic address: yhua@uwyo.edu.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, School of Pharmacy, College of Health Sciences, Laramie, WY 82071, USA. Electronic address: sreejay@uwyo.edu.
authors.forename: Sreejayan
authors.initials: S
authors.lastname: Nair
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D006801:Humans; D008659:Metabolic Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D011480:Protease Inhibitors; D010447:Peptide Hydrolases
keywords: Calpain; Cardiometabolic diseases; Caspase; Cathepsin; MMP