Hypoxia-inducible factor-1α in cardiovascular disease, mechanistic insights, pathophysiological roles, and therapeutic targeting strategies.

Hypoxia-inducible factor-1α (HIF-1α) is a critical mediator of hypoxic response at the transcriptional level and an emerging player in cardiovascular disease (CVD). Under normoxic conditions, HIF-1α undergoes prolyl hydroxylase (PHD)-mediated hydroxylation, which promotes its recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase and subsequent proteasomal degradation. In contrast, hypoxic conditions inhibit this degradation pathway, leading to stabilization of HIF-1α, its nuclear translocation, heterodimerization with HIF-1β, and activation of transcriptional programs that regulate angiogenesis, glycolysis, erythropoiesis, and cell survival. In various cardiovascular disease, including ischemic heart disease, myocardial infarction, heart failure, and pulmonary hypertension, HIF-1α exhibits a dual nature: while transient activation elicits adaptive responses (angiogenesis, metabolic reprogramming), sustained or dysregulated activation underlies maladaptive remodeling, fibrosis, and arrhythmogenesis. Recent studies have highlighted the promise of pharmacological modulators of HIF-1α (prolyl hydroxylase inhibitors, small natural chemicals, gene therapy, nanoparticles) to restore oxygen homeostasis and enable cardiac repair. However, concerns of off-target effects and carcinogenesis have yet to be overcome. In this review, we provide an up-to-date overview of HIF-1α signaling in the context of cardiac disease, including downstream effectors, disease pathogenesis, and potential therapeutic strategies. Targeting HIF-1α presents a promising strategy for cardiovascular therapies and warrants appropriate manipulation depending on the disease stage and environment.