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-1 alpha (HIF-1 alpha) maybe a key factor producing HFpEF. HIF-1 alpha, a highly conserved transcription factor that plays a key role in tissue response to hypoxia, is increased in adipose tissue in obesity. Increased HIF-1 alpha 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-1 alpha is also responsible for recruiting M1 macrophages that mediate obesity-associated inflammation, releasing IL-6, MCP-1, TNF-alpha, and IL-1 beta with increased expression of thrombospondin, pro alpha 2 (I) collagen, transforming growth factor beta, NADPH oxidase, and connective tissue growth factor. These factors can accelerate cardiac fibrosis and impair cardiac diastolic function. Inhibition of HIF-1 alpha 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-1 alpha in obesity-associated HFpEF may lead to new potential therapies.