Hypoxia-inducible factor 1-alpha (HIF-1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF), a common condition with an increased mortality, is strongly associated with obesity and the metabolic syndrome. The latter two conditions are associated with increased epicardial fat that can extend into the heart. This review advances the proposition that hypoxia-inhibitory factor-1α (HIF-1α) maybe a key factor producing HFpEF. HIF-1α, a highly conserved transcription factor that plays a key role in tissue response to hypoxia, is increased in adipose tissue in obesity. Increased HIF-1α expression leads to expression of a potent profibrotic transcriptional programme involving collagen I, III, IV, TIMP, and lysyl oxidase. The net effect is the formation of collagen fibres leading to fibrosis. HIF-1α is also responsible for recruiting M1 macrophages that mediate obesity-associated inflammation, releasing IL-6, MCP-1, TNF-α, and IL-1β with increased expression of thrombospondin, pro α2 (I) collagen, transforming growth factor β, NADPH oxidase, and connective tissue growth factor. These factors can accelerate cardiac fibrosis and impair cardiac diastolic function. Inhibition of HIF-1α expression in adipose tissue of mice fed a high-fat diet suppressed fibrosis and reduces inflammation in adipose tissue. Delineation of the role played by HIF-1α in obesity-associated HFpEF may lead to new potential therapies.