Expressing an inhibitor of PLCß1b sustains contractile function following pressure overload.

ABSTRACT

The activity of phospholipase Cß1b (PLCß1b) is selectively elevated in failing myocardium and cardiac expression of PLCß1b causes contractile dysfunction. PLCß1b can be selectively inhibited by expressing a peptide inhibitor that prevents sarcolemmal localization. The inhibitory peptide, PLCß1b-CT was expressed in heart from a mini-gene using adeno-associated virus (rAAV6-PLCß1b-CT). rAAV6-PLCß1b-CT, or blank virus, was delivered IV (4×10(9)vg/g body weight) and trans-aortic-constriction (TAC) or sham-operation was performed 8weeks later. Expression of PLCß1b-CT prevented the loss of contractile function, eliminated lung congestion and improved survival following TAC with either a 'moderate' or 'severe' pressure gradient. Hypertrophy was attenuated but not eliminated. Expression of the PLCß1b-CT peptide 2-3weeks after TAC reduced contractile dysfunction and lung congestion, without limiting hypertrophy. PLCß1b inhibition ameliorates pathological responses following acute pressure overload. The targeting of PLCß1b to the sarcolemma provides the basis for the development of a new class of inotropic agent.