Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cardiac Fibroblast Biology

Background:

• Myocardial infarction (MI) is a major cause of death, with cardiac rupture being a severe complication.
• Akt signaling pathways are implicated in various cardiac diseases.
• The specific role of Girdin (also known as KIAA1530) and its Akt-mediated phosphorylation in MI pathogenesis remained unclear.

Purpose of the Study:

• To investigate the role of Girdin expression and phosphorylation at serine 1416 in the context of acute myocardial infarction.
• To elucidate the mechanism by which Akt/Girdin signaling influences cardiac repair and cardiac rupture post-MI.

Main Methods:

• Utilized Girdin-deficient mice and Girdin S1416A knock-in (Girdin(SA/SA)) mice, where the Akt phosphorylation site is mutated to alanine.
• Assessed Girdin expression and phosphorylation in cardiac fibroblasts in vitro.
• Analyzed cardiac myofibroblast accumulation, proliferation, collagen deposition, and cardiac rupture in an acute myocardial infarction mouse model.

Main Results:

• Girdin phosphorylation was essential for cardiac fibroblast proliferation and migration in vitro.
• In vivo, Girdin was phosphorylated in cardiac myofibroblasts (α-smooth muscle actin-positive cells).
• Girdin(SA/SA) mice exhibited suppressed cardiac myofibroblast accumulation and proliferation in the infarcted area, leading to reduced collagen deposition, impaired cardiac repair, and increased mortality due to cardiac rupture.

Conclusions:

• Girdin phosphorylation at serine 1416 plays a critical role in cardiac repair following acute myocardial infarction.
• The Akt/Girdin signaling pathway regulates cardiac myofibroblasts, influencing cardiac repair and susceptibility to rupture.
• Targeting Akt/Girdin phosphorylation may offer therapeutic strategies for improving outcomes after myocardial infarction.