Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves...

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Metabolic Signaling

Background:

• Prolonged cardiac stress requires coordinated signaling and gene expression changes to maintain function.
• Loss of steroid receptor coactivator-2 (SRC-2) in mice leads to a fetal gene program reversal and impaired response to pressure overload.
• SRC-2 deficiency is associated with metabolic alterations and increased AMP-activated protein kinase (AMPK) activation.

Purpose of the Study:

• To investigate if early metabolic stress, driven by AMPK activation, causes contractile dysfunction in SRC-2-deficient mice.
• To determine the effects of transient AMPK activation before pressure overload on cardiac function and remodeling in wild-type and SRC-2 knockout mice.

Main Methods:

• Utilized 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to transiently activate AMPK.
• Administered AICAR before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) mice.
• Assessed molecular signaling (Akt, NAD+, antioxidant pathways), cardiac remodeling (fibrosis, hypertrophy), and cardiac function.

Main Results:

• In unstressed hearts, AICAR induced mild Akt activation, partially relieved NAD+ deficiency, and increased antioxidant signaling in SRC-2-CKO mice.
• Prestress AMPK activation led to a mild hypertrophic response to TAC with reduced maladaptive remodeling and significantly decreased fibrosis.
• SRC-2-CKO mice with preactivated AMPK showed dramatically improved cardiac function compared to saline-treated controls after TAC.

Conclusions:

• Altered molecular signaling prior to stress onset has lasting effects on sustained cardiac stress responses.
• Prestress modulation of transient growth and metabolism pathways can significantly influence cardiac stress resilience.
• Transient AMPK activation before pressure overload represents a potential therapeutic strategy to mitigate adverse cardiac remodeling and preserve function.