Protein Kinase C – Possible Therapeutic Target to Treat Cardiovascular Diseases

Yamini      S. Bynagari-Settipalli; Ramya      Chari; Laurie      Kilpatrick; Satya      P. Kunapuli

Abstract

Cardiovascular diseases (CVDs) such as atherosclerosis, hypertension and diabetes, are major global health problems and one of the leading causes of death. Thrombosis associated with multiple CVDs such as atherosclerosis and diabetes further increase morbidity by causing myocardial infarction or stroke. The members of Protein Kinase C (PKC) family are serine threonine kinases, abundantly expressed in cells that maintain cardiovascular health. Studies done using pharmacological tools that block wide range of PKCs or specific PKC isoforms and PKC gene knockout animals revealed that these enzymes regulate critical functional responses in cardiovascular cells. Interestingly, PKC isotype activity is context specific and PKC isotypes may have opposing functional roles depending on cell type and cellular environment (eg., cardiomyocytes, platelets). Furthermore, precise structural differences that occur amongst these isoforms have lead to development of compounds that inhibit or activate specific PKC isoforms. Thus, it is feasible to enhance the protective effects of a PKC isoform, while minimizing the damage caused by other members of PKC family. In this review, we summarize the role of each of these PKC isoforms in various cardiovascular diseases. In addition, we detail the specific PKC isoform modulators, their mechanism of action and ability to treat cardiovascular diseases, as evaluated in animal models or human subjects.

Keywords: Protein kinase C, cardiovascular diseases, thrombosis, atherosclerosis, metabolic syndrome, stroke, Cardiovascular diseases (CVDs), Protein Kinase C (PKC), serine threonine kinases, cardiomyocytes, platelets, hypertension, myocardial infarction, angina pectoris, pulmonary embolism, isozymes, Pseudosubstrate domain, domain binds diacylglycerol (DAG), phosphatidyl serine, protein, protein interactions, pleckstrin homology, phosphoinositide-3, 4, 5- trisphosphate (PIP3), phosphoinositol-4, 5-bisphosphate (PIP2), Phosphorylation, heat shock proteins, Src Family Kinases (SFKs), Phospholipase C, diacyl glycerol kinases, proteases, calpain, ubiquitination, proteosomal, E3 ligase, benzolactams, myeloid Leukemia, interleukin, calcium ionophore, mycelia, Actinomycetes, Bryostatin1, Fludarabine, Lymphoma, Leukemia, bryostatin, Staurosporine, Streptomyces, Calphostin C, Cladosporium cladosporides, Bisindolylmaleimides, oedema, Diazoxide, pseudosubstrate, myristoylated, Low Density Lipids (LDL), oxidized LDL (oxLDL), vascular smooth muscle cells (VSMCs), T-lymphocytes, bymatrix metalloproteinases (MMPs), neurologic disease, G-protein, von willebrand factor, phorbol myristate acetate, Wiskott-Aldrich syndrome protein (WASP)