Abstract 337: Reversal of Pathological Responses to Pressure Overload by Inhibition of Phospholipase Cbeta1b
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Abstract
The immediate downstream effector of Galpahq is the early signaling enzyme phospholipase Cbeta1b (PLCbeta1b), which is selectively elevated in failing human myocardium. When delivered to the adult mouse heart, expression of PLCbeta1b causes rapid contractile dysfunction. PLCbeta1b targets to the sarcolemma for activation through an interaction with Shank3/Homer1C/TrpC4α using a specific C-terminal sequence of 32aa. The targeting/activity of PLCbeta1b can be inhibited by expression of a sarcolemmal targeted mini-gene composed of this 32aa sequence (lyn-FLAG-PLCbeta1b-CT, b-CT). rAAV6-b-CT, or blank virus, was delivered IV (1011vg/mouse) and trans-aortic-constriction (TAC) or sham-operation was performed 8 weeks later. TAC induced maximal hypertrophy by 8 weeks after TAC, followed by contractile dysfunction and lung congestion from 16 weeks. Expression of rAAV6-b-CT prior to TAC reduced the hypertrophic response and prevented the contractile dysfunction and lung congestion. Expressing a modified b-CT peptide that does not inhibit PLCbeta1b signaling had no effect on hypertrophy, contractility or lung congestion following TAC. We conclude that PLCbeta1b can be effectively targeted by preventing its binding to the sarcolemma and that this inhibition ameliorates pathological responses following acute pressure overload. The binding of PLCbeta1b to its sarcolemmal scaffold provides the basis for the development of a new class of inotropic agent.

Author Disclosures: D.R. Grubb: None. H. Kiriazis: None. X. Du: None. J. McMullen: None. E. Woodcock: None.
- © 2015 by American Heart Association, Inc.
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- Abstract 337: Reversal of Pathological Responses to Pressure Overload by Inhibition of Phospholipase Cbeta1bDavid R Grubb, Helen Kiriazis, Xiao-jun Du, Julie McMullen and Elizabeth WoodcockCirculation Research. 2015;117:A337, originally published October 21, 2015
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