Loss of cardiac phosphoinositide 3-kinase p110 alpha results in contractile dysfunction

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Cell Signaling

Background:

• Phosphoinositide 3-kinase (PI3K) p110alpha is crucial for insulin action and cancer.
• Myocyte contraction depends on L-type calcium current (I(Ca,L)) via L-type calcium channels (LTCCs).

Purpose of the Study:

• To investigate if PI3K p110alpha regulates cardiac contractility by modulating LTCCs.

Main Methods:

• Genetic ablation of p110alpha and p110beta in adult mouse cardiac myocytes.
• Pharmacological inhibition of p110alpha and p110beta in canine myocytes.
• Measurement of I(Ca,L), LTCC surface expression, and cardiac function.

Main Results:

• Genetic deletion of p110alpha, not p110beta, reduced I(Ca,L) and blocked cardiac insulin signaling in mice.
• p110alpha-null myocytes showed fewer LTCCs on the cell surface, leading to contractile defects and reduced in vivo cardiac function.
• Pharmacological inhibition of p110alpha, but not p110beta, decreased I(Ca,L) and contractility in canine myocytes.

Conclusions:

• PI3K p110alpha, but not p110beta, is a key regulator of LTCCs in cardiac myocytes.
• Reduced p110alpha signaling diminishes LTCCs at the cell surface, attenuating I(Ca,L) and cardiac contractility.