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

Abstract

Summary 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.

Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys

“…The 67 genes downstream of TFs with significantly higher expression in the mNIA diet compared with the NIA diet were also significantly overrepresented in the PI3K/Akt pathway (9 genes, FDR = 0.002). Increased HIF-1 expression is associated with upregulation of collagen isoforms and TIMPs in the heart, leading to increased fibrosis (51). The PI3K/ Akt pathway plays a key role in cardiac hypertrophy regulation of cardiac titin, stiffness, and angiogenesis (52).…”

Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

“…Impaired glucose metabolism, increased lipid accumulation and ROS levels might cause hypoxia and chronic pathological expression level of HIF-1α in the heart ( Warbrick and Rabkin, 2019 ; Movafagh et al., 2015 ). Chronic activation of HIF-1α was responsible for recruiting M1 macrophages in the heart and mediated metabolic inflammation in cardiomyocytes, thereby releasing IL-6, MCP-1, TNF-α, and IL-1β; NADPH oxidase; and connective tissue growth factor; the resulting chronic inflammation accelerated cardiac fibrosis and impaired the cardiac diastolic function ( Warbrick and Rabkin, 2019 ) ( Warbrick and Rabkin, 2019 ). Recently, research found that knock out of HIF-1α protected HF in the animal model ( Kumar et al, 2018 ).…”

Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes and Protects Diabetic Mouse Hearts by Targeting the mTOR/HIF-1α Pathway

“…Impaired glucose metabolism, increased lipid accumulation and ROS levels might cause hypoxia and chronic pathological expression level of HIF-1α in the heart (43) (44). Chronic activation of HIF-1α was responsible for recruiting M1 macrophages in the heart and mediated metabolic in ammation in cardiomyocytes, thereby releasing IL-6, MCP-1, TNF-α, and IL-1β, NADPH oxidase, and connective tissue growth factor; the resulting chronic in ammation accelerated cardiac brosis and impaired the cardiac diastolic function (43) (45). Recently, research found that knockout of HIF-1α protected HF in the animal model (9).…”