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(Circulation. 2009;120:318-325.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Loss of Cardiac Phosphoinositide 3-Kinase p110 Results in Contractile Dysfunction

Zhongju Lu, PhD^*; Ya-Ping Jiang, MD^*; Wei Wang, PhD; Xin-Hua Xu, MD; Richard T. Mathias, PhD; Emilia Entcheva, PhD; Lisa M. Ballou, PhD; Ira S. Cohen, MD, PhD; Richard Z. Lin, MD

From the Department of Physiology and Biophysics and Institute of Molecular Cardiology (Z.L., W.W., R.T.M., E.E., I.S.C., R.Z.L.) and Department of Medicine (Y.P.J., L.M.B., R.Z.L.), Stony Brook University, Stony Brook, NY; Department of Cardiac Surgery, Central South University, Changsha, China (X.H.X.); and Department of Veterans Affairs Medical Center, Northport, NY (R.Z.L.).

Correspondence to Dr Richard Z. Lin, Division of Hematology/Oncology, HSC T15–045, Stony Brook University, Stony Brook, NY 11794–8151. E-mail richard.lin{at}sunysb.edu

Received August 14, 2009; accepted May 5, 2009.

Background— Phosphoinositide 3-kinase (PI3K) p110 plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca²⁺ current (I_Ca,L) through the voltage-dependent L-type Ca²⁺ channel (LTCC). The aim of this study was to evaluate whether p110 also controls cardiac contractility by regulating the LTCC.

Methods and Results— Genetic ablation of p110 (also known as Pik3ca), but not p110β (also known as Pik3cb), in cardiac myocytes of adult mice reduced I_Ca,L and blocked insulin signaling in the heart. p110-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110 decreased I_Ca,L and contractility in canine myocytes. Inhibition of p110β did not reduce I_Ca,L.

Conclusions— PI3K p110 but not p110β regulates the LTCC in cardiac myocytes. Decreased signaling to p110 reduces the number of LTCCs on the cell surface and thus attenuates I_Ca,L and contractility.

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Clinical Summaries
Circulation 2009 120: 267-268. [Extract] [Full Text]