Potential treatment of cardiac hypertrophy and heart failure by inhibiting the sarcolemmal binding of phospholipase Cbeta1b.
Heart failure, the common end-point of many cardiac diseases, is a major contributor to mortality and morbidity and contributes considerably to health care costs. Current treatment regimens include beta-adrenergic antagonists, angiotensin converting enzyme inhibitors, and inotropic agents are used by some patients. Studies in experimental animals have demonstrated that inhibition of signaling pathways downstream of the heterotrimeric G protein Gq reduce ventricular hypertrophy and protects from the development of heart failure. However, targets identified, to date, have been limited by a lack of tissue specificity. In cardiomyocytes, Gq activates only one splice variant of one subtype of phospholipase Cbeta, specifically phospholipase Cbeta1b (PLCbeta1b) and PLCbeta1b is responsible for Gq mediated hypertrophic and apoptotic responses. PLCbeta1b targets to the sarcolemma via its unique C-terminal sequence and its activation can be inhibited by expressing the C-terminal sequence to compete for sarcolemmal binding. Inhibition of PLCbeta1b by the C-terminal peptide reduces hypertrophic responses in cardiomyocytes. We present the evidence that inhibition of the sarcolemmal association of PLCbeta1b provides a cardiac-specific target for the development of drugs to reduce pathological cardiac hypertrophy and thereby to reduce the burden of heart failure.
Woodcock
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Molecular Cardiology Laboratory,Baker IDI Heart and Diabetes Institute, St. Kilda Road Central, Melbourne 8008, Victoria, Australia. liz.woodcock@bakeridi.edu.au
Grubb
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Iliades
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D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D015195:Drug Design; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D054799:Phospholipase C beta / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction
D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11