Unveiling the role of extracellular nucleic acids in hypoxia-induced myocardial injury

Cardiovascular diseases (CVDs), particularly myocardial infarction (MI), have been linked to hypoxia-induced cellular stress, independent of infectious factors. Hypoxia triggers the release of endogenous ligands from necrotic cells, including circulating nucleic acids (CNAs) like extracellular RNA (eRNA) and DNA (eDNA), which activate Toll-like receptors (TLRs) and exacerbate inflammation. Elevated CNAs in plasma, released due to hypoxic stress and ischemia/reperfusion injuries, have been correlated with increased tissue damage and clinical manifestations such as coronary artery disease (CAD) and chest pain.

Our study explores the mechanistic role of hypoxia in promoting sterile inflammation, driven by cellular damage-associated molecular patterns (DAMPs) like eRNA. These DAMPs activate the innate immune system, contributing to vascular inflammation, particularly in MI. We investigated the role of eRNA and TLR3 in mediating cardiomyocyte necrosis and subsequent cTroponin-T (cTrop-T) release—a known marker of acute myocardial infarction (AMI).

Key findings include: (i) Hypoxia stimulates eRNA release, promoting MI through a TLR3-caspase-3 pathway, as evidenced by time-dependent increases in cTrop-T levels. (ii) RNaseA pre-treatment significantly reduced plasma cTrop-T levels, while DNase1 and HMGB1 neutralizing antibodies showed no such effect. (iii) Inhibition of TLR3 via neutralizing antibodies or gene silencing also reduced cTrop-T release, confirming TLR3 involvement in hypoxia-induced myocardial injury. (iv) The role of eRNA-TLR3 interaction was further validated by its contribution to leukocyte infiltration, neutrophil activation, and cardiomyocyte necrosis, leading to myocardial stiffness, dysfunction, and eventual heart failure.

Our findings suggest that therapeutic approaches targeting eRNA, such as RNaseA treatment or TLR3 silencing, could mitigate myocardial damage in hypoxia-induced CVDs. This study opens avenues for novel therapies aimed at preventing AMI and heart failure by addressing hypoxia-induced sterile inflammation pathways.

Dr. Gausal Azam Khan, PhD, CSci, FRSM, FRSB, is a Professor of Clinical Nutrition at King Faisal University, Saudi Arabia. His research spans insulin resistance, endothelial dysfunction, thrombosis, and preeclampsia. He holds multiple US patents, including a vaccine for Type 2 Diabetes, and has received prestigious awards such as the Chartered Scientist, FRSB, FRSM and IFUPS. With a prolific academic output including over 100 international publications and numerous invited talks worldwide, he has secured major research grants across India, Canada, and Saudi Arabia. Dr. Khan’s contributions advance understanding of metabolic and vascular pathophysiology under hypoxic stress and inflammation.