4,8-Dicarboxyl-8,9-Iridoid-1-Glycoside Alleviates Cardiac Dysfunction After Myocardial Ischaemia-Reperfusion Injury...

Area of Science:

• Cardiovascular Research
• Fibrosis Research
• Pharmacology

Background:

• Extracellular matrix (ECM) deposition and fibrosis impair cardiac function post-myocardial ischemia-reperfusion injury (I/RI).
• Current therapeutic strategies for inhibiting ECM deposition and fibrosis remain limited.
• Type VI collagen-alpha 3 (Col6a3) overexpression in fibroblasts promotes myocardial fibrosis.

Purpose of the Study:

• To investigate the therapeutic potential of 4,8-dicarboxyl-8,9-iridoid-1-glycoside (BIG) in mitigating myocardial fibrosis and dysfunction following I/RI.
• To elucidate the underlying molecular mechanisms of BIG's action, including its effect on collagen deposition and inflammatory pathways.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) identified Col6a3 as a key factor in fibrosis.
• In vivo studies utilized echocardiography, TTC, and Evans blue staining to assess cardiac function and infarct size in I/RI mice treated with BIG.
• In vitro experiments and immunofluorescence staining evaluated the effects of BIG on inflammatory responses, apoptosis, TGF-β, and Col6a3 expression.
• The PI3K/AKT pathway was investigated using specific inhibitors (LY294002) to confirm BIG's mechanism of action.

Main Results:

• BIG treatment alleviated cardiac dysfunction and reduced myocardial infarction size and area at risk in mice subjected to I/RI.
• BIG inhibited inflammatory responses, apoptosis, and matrix metalloproteinase (MMP) secretion both in vivo and in vitro.
• BIG downregulated TGF-β and Col6a3 expression in cardiac fibroblasts, suggesting a direct antifibrotic effect.
• BIG's therapeutic effects were mediated by the activation of the PI3K/AKT pathway.

Conclusions:

• BIG demonstrates significant therapeutic potential in reducing collagen deposition and treating myocardial fibrosis induced by I/RI.
• BIG alleviates cardiac dysfunction post-I/RI by inhibiting fibrosis through the activation of the PI3K/AKT pathway.
• These findings provide valuable insights for developing novel therapeutic strategies targeting myocardial fibrosis.