Deficiency of miR-409-3p improves myocardial neovascularization and function through modulation of DNAJB9/p38 MAPK...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Metabolic Regulation

Background:

• Angiogenesis is crucial for tissue repair post-myocardial infarction (MI), but is impaired by insulin resistance and diabetes.
• MicroRNAs (miRNAs) are key regulators of angiogenesis, influencing cellular processes vital for vascularization.
• The specific role of miR-409-3p in metabolic regulation of post-MI angiogenesis remains underexplored.

Purpose of the Study:

• To investigate the metabolic regulation of miR-409-3p in endothelial cells (ECs) following myocardial infarction (MI).
• To elucidate the functional role of miR-409-3p in ECs during the angiogenic response to ischemia.
• To identify downstream targets and signaling pathways regulated by miR-409-3p in the context of cardiac repair.

Main Methods:

• Expression analysis of miR-409-3p in human acute coronary syndrome (ACS) patients and a mouse MI model.
• In vitro studies using endothelial cells (ECs) treated with palmitate, VEGF, and FGF to assess miR-409-3p regulation and function.
• RNA sequencing (RNA-seq) and Argonaute2 immunoprecipitation to identify miR-409-3p targets, with validation of DNAJB9.
• Generation and physiological assessment of EC-specific miR-409-3p knockout (miR-409^ECKO) mice on a high-fat, high-sucrose diet undergoing ischemia-reperfusion (I/R) injury.

Main Results:

• miR-409-3p expression was elevated in ACS patients and post-MI mice, induced by palmitate in ECs, and suppressed by VEGF/FGF.
• Overexpression of miR-409-3p inhibited EC proliferation and migration, while its inhibition promoted these processes.
• DNAJB9 was identified as a direct target of miR-409-3p, with its expression regulated via the p38 MAPK pathway.
• In miR-409^ECKO mice, knockout of miR-409-3p in ECs significantly enhanced angiogenesis markers (isolectin B4, CD31) and DNAJB9 levels post-I/R injury.
• Cardiac function was improved, evidenced by increased ejection fraction (EF) and reduced infarct size in miR-409^ECKO mice compared to controls.

Conclusions:

• miR-409-3p plays a detrimental role in the angiogenic response to myocardial ischemia, particularly under metabolic stress.
• Targeting miR-409-3p in endothelial cells represents a promising therapeutic strategy to promote cardiac repair after MI.
• The findings highlight miR-409-3p as a critical mediator linking metabolic dysfunction to impaired angiogenesis in heart disease.