Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• DNA Damage Response

Background:

• Ataxia telangiectasia-mutated kinase (ATM) is a key protein in DNA damage and oxidative stress response.
• ATM deficiency is linked to early post-myocardial infarction (MI) apoptosis, fibrosis, and attenuated cardiac dysfunction.
• Previous findings suggest ATM plays a role in cardiac repair following injury.

Purpose of the Study:

• To investigate if ATM deficiency exacerbates cardiac dysfunction and remodeling late post-MI.
• To determine the impact of ATM deficiency on fibrosis, apoptosis, and myocyte hypertrophy in the late stages of cardiac repair.
• To test the hypothesis that early-stage ATM deficiency effects worsen late-stage cardiac outcomes.

Main Methods:

• Myocardial infarction (MI) induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice.
• Echocardiography assessed left ventricular (LV) structure and function at 14 and 28 days post-MI.
• Biochemical analyses measured fibrosis, myocyte size, apoptosis markers, and matrix metalloproteinases (MMPs).

Main Results:

• hKO-MI mice showed exacerbated LV dysfunction, increased LV end-systolic volume, and reduced fractional shortening and ejection fraction.
• Increased fibrosis and α-smooth muscle actin expression were observed in hKO-MI hearts.
• Myocyte cross-sectional area was greater in hKO-MI mice; apoptosis and GSK-3β activation were lower.
• MMP-9 expression was reduced in the noninfarct region of hKO-MI mice.

Conclusions:

• ATM deficiency exacerbates cardiac remodeling and dysfunction late after myocardial infarction.
• ATM deficiency impacts cardiac function, fibrosis, apoptosis, and myocyte hypertrophy post-MI.
• These findings highlight ATM's critical role in long-term cardiac repair and remodeling following ischemic injury.