Soluble Receptor for Advanced Glycation End-products regulates age-associated Cardiac Fibrosis

Area of Science:

• Cardiovascular Biology
• Aging Research
• Molecular Medicine

Background:

• Myocardial aging elevates cardiovascular risk in older adults.
• The Receptor for Advanced Glycation End-products (RAGE) pathway is implicated in age-related diseases.
• Soluble RAGE (sRAGE) acts as a decoy receptor, mitigating RAGE signaling.

Purpose of the Study:

• To investigate the role of RAGE in age-dependent cardiac remodeling.
• To determine the impact of RAGE deficiency on cardiac structure and function during aging.
• To explore the potential of sRAGE as a therapeutic agent against cardiac fibrosis.

Main Methods:

• Comparative analysis of cardiac function, fibrosis, and cellular markers in young, middle-aged, and old RAGE-deficient (Rage-/-) and wild-type (WT) female mice.
• Assessment of pro-fibrotic pathway components (TGF-β1) and RAGE isoform expression in cardiac tissue.
• In vitro studies using human cardiac fibroblasts treated with sRAGE.
• In vivo administration of sRAGE to middle-aged WT mice.

Main Results:

• Rage-/- mice exhibited exacerbated age-dependent increases in left ventricle dimensions and cardiac fibrosis compared to WT mice.
• Rage-/- mice showed increased α-Smooth Muscle Actin (SMA)+ cells and elevated expression of TGF-β1 pathway components.
• Circulating sRAGE levels decreased with aging and correlated inversely with left ventricle diastolic dimensions.
• sRAGE treatment reduced cardiac fibroblast proliferation, pro-fibrotic protein expression, and TGFbR1/Smad2-3 activation, and attenuated cardiac fibrosis in vivo.

Conclusions:

• RAGE signaling is integral to age-dependent myocardial changes.
• Reduced circulating sRAGE levels are associated with cardiac aging and fibrosis.
• sRAGE acts as a potent inhibitor of cardiac fibroblast differentiation and age-related cardiac fibrosis, suggesting therapeutic potential.