HIF Activation Against CVD in CKD: Novel Treatment Opportunities

Cardiovascular disease is a common and serious complication in patients with chronic kidney disease (CKD). One of the fundamental functions of the cardiovascular system is oxygen delivery, therefore cardiovascular disease inherently is linked to insufficient tissue oxygenation. Advances in our knowledge of cellular oxygen sensing by a family of prolyl hydroxylases (PHDs) and their role in regulating hypoxia-inducible factors (HIFs) have led to the discovery of PHD inhibitors as HIF stabilizers. Several small-molecule PHD inhibitors are currently in clinical trials for the treatment of anemia in CKD. An additional advantage of PHD inhibition may be found in the potential impact on cardiovascular consequences associated with CKD. Several preclinical studies have suggested a potential benefit of HIF activation in myocardial infarction, cardiac remodeling, atherosclerosis, and peripheral artery disease. Ameliorating glucose and lipid metabolism and lowering blood pressure may also contribute to cardiovascular protection. On the other hand, the broad spectrum of HIF-dependent functions also may include unwanted side effects. Clinical application of PHD inhibitors therefore necessitates careful evaluation of the net systemic effect of HIF activation.