Mechanistic investigation of quercetin (an active component of RAS-RH) in modulating radiation-induced coronary...

Coronary Microvascular Dysfunction (CMVD), a prevalent comorbidity of various cardiovascular diseases, may contribute to myocardial cell ischemic necrosis. The loss of microvessels-driven by endothelial cells (ECs) apoptosis-is the core pathological hallmarks of CMVD. Our previous studies have established that RAS-RH (Angelica sinensis and Astragalus membranaceus ultrafiltrate) promotes angiogenesis and improves cardiac perfusion. However, its underlying molecular mechanisms remain incompletely understood.

This study aimed to elucidate the key mechanism by which quercetin, the primary active component of RAS-RH, modulates radiation-induced ECs apoptosis.

Through the integration of network pharmacology and transcriptomics, we identified potential active components of RAS-RH and their key targets involved in regulating the telocytes-endothelial cell (TCs-ECs) crosstalk pathway underlying CMVD. These predictions were further validated using in vitro cellular models via flow cytometry, western blot, wound-healing assays, in situ hybridization, immunofluorescence staining, and EdU proliferation assays.

Consistent with our predictions, experimental results demonstrated that quercetin (the primary active component of RAS-RH) significantly upregulated the expression of HIF-1α and miRNA-126 in TCs (P < 0.01) and enhanced miRNA-126 paracrine secretion. Through this paracrine mechanism, quercetin downregulated the expression of Cypd, ANT, F1F0-ATPase, and VDAC in ECs (P < 0.01), inhibited the reduction of mitochondrial membrane potential (ΔΨm) and ECs apoptosis induced by excessive mPTP opening. Collectively, these effects enhanced ECs proliferation, migration, and tube formation capacity, ultimately promoting angiogenesis.

These results collectively demonstrate that quercetin, the primary active component of RAS-RH, suppresses excessive mPTP activation and apoptosis while stimulating ECs migration and tube formation. This occurs via upregulating HIF-1α and miRNA-126 expression in TCs and enhancing miRNA-126 paracrine to ECs, positioning the TCs-ECs crosstalk mechanism as a promising novel therapeutic target for intervening in coronary microcirculation dysfunction.