Molecular basis and clinical implications of HIFs in cardiovascular diseases

The spatiotemporal specificity of myocardial hypoxia-inducible factors (HIFs) appears in response to acute and chronic hypoxia (including degree of hypoxia) and is modulated by distant neurohumoral forces. Further, transitions between HIF-α isoforms in cardiomyocytes may regulate protection from myocardial dysfunction. Disturbances in circadian rhythms are also considered because the spatiotemporal specificity of HIF correlates with the myocardial injury response: shiftwork patients are more likely to have myocardial infarction and possibly a larger infarct size. The therapeutic goal of injured myocardium is to safeguard surviving cardiomyocytes, improve their function, or even stimulate their regenerative potential. Precisely targeted small-molecule candidates for HIF or combinations based on the HIF mechanism may reduce toxicity and increase the efficacy of myocardial protection. Oxygen maintains the homeostasis of an organism in a delicate balance in different tissues and organs. Under hypoxic conditions, hypoxia-inducible factors (HIFs) are specific and dominant factors in the spatiotemporal regulation of oxygen homeostasis. As the most basic functional unit of the heart at the cellular level, the cardiomyocyte relies on oxygen and nutrients delivered by the microvasculature to keep the heart functioning properly. Under hypoxic stress, HIFs are involved in acute and chronic myocardial pathology because of their spatiotemporal specificity, thus granting them therapeutic potential. Most adult animals lack the ability to regenerate their myocardium entirely following injury, and complete regeneration has long been a goal of clinical treatment for heart failure. The precise manipulation of HIFs (considering their dynamic balance and transformation) and the development of HIF-targeted drugs is therefore an extremely attractive cardioprotective therapy for protecting against myocardial ischemic and hypoxic injury, avoiding myocardial remodeling and heart failure, and promoting recovery of cardiac function. Oxygen maintains the homeostasis of an organism in a delicate balance in different tissues and organs. Under hypoxic conditions, hypoxia-inducible factors (HIFs) are specific and dominant factors in the spatiotemporal regulation of oxygen homeostasis. As the most basic functional unit of the heart at the cellular level, the cardiomyocyte relies on oxygen and nutrients delivered by the microvasculature to keep the heart functioning properly. Under hypoxic stress, HIFs are involved in acute and chronic myocardial pathology because of their spatiotemporal specificity, thus granting them therapeutic potential. Most adult animals lack the ability to regenerate their myocardium entirely following injury, and complete regeneration has long been a goal of clinical treatment for heart failure. The precise manipulation of HIFs (considering their dynamic balance and transformation) and the development of HIF-targeted drugs is therefore an extremely attractive cardioprotective therapy for protecting against myocardial ischemic and hypoxic injury, avoiding myocardial remodeling and heart failure, and promoting recovery of cardiac function. a family of dimeric transcription factors composed of combinations of JUN, FOS, ATF, JDP, and MAF. AP-1 components are encoded by immediate-early genes and regulate the later-phase transcriptional program for tumorigenesis and organ maintenance. an L-type calcium channel (LTCC) that controls ICa,L in the ventricular myocardium where it mediates excitation–contraction coupling and Ca2+ induced-Ca2+ release (termed Ca2+ sparks). under prolonged low perfusion, the myocardium reduces energy expenditure and contractile function to resist ischemic injury and improve its survival rate. the inwardly rectifying K+ current IK1 is a crucial predictor of cardiac resting membrane potential and repolarization in the terminal phase of the ventricular action potential. Kir2.x channels support cardiac IK1, and Kir2.1 (encoded by the KCNJ2 gene) contributes more to ventricular cardiomyocytes than Kir2.2. a nonselective pore in the mitochondrial inner membrane that can cause ATP depletion, accelerated generation of reactive oxygen species (ROS), mitochondrial malfunction, and ultimately cell death. a key voltage-gated cardiac sodium channel, encoded by SCN5A, that controls INa and conducts cardiac excitatory electrical impulses and propagation. the cell-membrane NCX maintains Ca2+ homeostasis and controls INa/Ca. transient ischemia of peripheral organs or distal limbs can protect against ischemia/reperfusion (I/R) injury of target organs (e.g., the heart). This intermittent preconditioning can be sustained by daily exposure to hypoxia at atmospheric or low pressure or by multiple cycles of reoxygenation following a few minutes of hypoxia at atmospheric pressure. in RISK pathways, IL-10, PI3K–AKT, and ERK1/2 are elevated in the heart for cardioprotection. Downstream actions of the RISK pathways converge on GSK-3β, whose inhibition precludes MPTP opening. following complete recovery of coronary blood flow after a brief bout of myocardial ischemia, the contractile dysfunction of the myocardium is disproportionately long-lasting (hours to days), but completely reversible. TNF-α, its receptor subtype 2, and STAT3 are expressed in the cardioprotective SAFE system. STAT signaling, although acutely protective, is also engaged in long-term remodeling and malfunction of the heart.