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Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors?

ABSTRACT: Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes. Diabetes is associated with either an insulin deficiency in its juvenile form or with insulin resistance and obesity in Type 2 diabetes mellitus, and the latter is clustered with other comorbidities to define the metabolic syndrome. Diabetes and metabolic syndrome are complex pathologies and are associated with cardiovascular risk via vascular inflammation and other mechanisms. Several transcription factors are activated upon diabetes-driven endothelial dysfunction and drive the progression of atherosclerosis. In particular, the hypoxia-inducible factor (HIF) transcription factor family is a master regulator of endothelial biology and is raising interest in the field of atherosclerosis. In this review, we will present an overview of studies contributing to the understanding of diabetes-driven atherosclerosis, integrating the role of HIF in this disease with the knowledge of its functions in metabolic syndrome and diabetic scenario.

SUBMITTER: Pirri D

PROVIDER: S-EPMC7441368 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors?

Pirri Daniela D Fragiadaki Maria M Evans Paul C PC

Bioscience reports 20200801 8

Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes. Diabetes is associated with either an insulin deficiency in its juvenile form or with insulin resistance and obesity in Type 2 diabetes mellitus, and the latter is clustered with other comorbidities to define the metabolic syndrome. Diabetes and metabolic syndrome are complex pathologies and are associated with cardiovascular risk via vascular inflammation and other mechanisms. Sev ...[more]

PMID: 32816039

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Project description:Background and aimsHypoxia inducible factor 1α (HIF1α) plays a critical role in atherosclerosis as demonstrated in endothelial-targeted HIF1α -deficient mice. However, it has not been shown if specific pharmacological inhibitors of HIF1α can be used as potential drugs for atherosclerosis. PX-478 is a selective inhibitor of HIF1α, which was used to reduce cancer and obesity in animal models. Here, we tested whether PX-478 can be used to inhibit atherosclerosis.MethodsWe first tested PX-478 in human aortic endothelial cells (HAEC) and found that it significantly inhibited expression of HIF1α and its targets, including Collagen I. Next, two independent atherosclerosis models, C57BL/6 mice treated with AAV-PCSK9 and ApoE-/- mice, were used to test the efficacy of PX-478. Both mouse models were fed a Western diet for 3 months with bi-weekly treatment with PX-478 (40 mg/kg) or saline.ResultsPX-478 treatment reduced atherosclerotic plaque burden in the aortic trees in both mouse models, while plaque burden in the aortic sinus was reduced in the AAV-PCSK9 mouse model, but not in the ApoE-/- mice. Russell-Movat's Pentachrome and Picrosirius Red staining showed a significant reduction in extracellular matrix remodeling and collagen maturation, respectively, in the PX-478-treated mice. As expected, PX-478 treatment reduced diet-induced weight-gain and abdominal adipocyte hypertrophy. Interestingly, PX-478 reduced plasma LDL cholesterol by 69% and 30% in AAV-PCSK9 and ApoE-/- mice, respectively. To explore the cholesterol-lowering mechanisms, we carried out an RNA sequencing study using the liver tissues from the ApoE-/- mouse study. We found 450 genes upregulated and 381 genes downregulated by PX-478 treatment in the liver. Further, gene ontology analysis showed that PX-478 treatment upregulated fatty acid and lipid catabolic pathways, while downregulating lipid biosynthesis and plasma lipoprotein particle remodeling processes. Of interest, Cfd, Elovl3, and Insig2 were some of the most downregulated genes by PX-478, and have been implicated in fat storage, fatty acid elongation, and cholesterol metabolism. The downregulation of Cfd, Elovl3, and Insig2 was further validated by qPCR in the liver tissues of ApoE-/- mice treated with PX-478.ConclusionsThese results suggest that PX-478 is a potential anti-atherogenic drug, which targets vascular endothelium and hepatic cholesterol pathways.

Dataset Information

Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors?

Publications

Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors?

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