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Rap1 in the Context of PCSK9, Atherosclerosis, and Diabetes

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Abstract

Purpose of Review

The focus of this article is to highlight the importance of the small GTPase, Ras-associated protein 1 (Rap1), in proprotein convertase subtilisin/kexin type 9 (PCSK9) regulation and atherosclerosis and type 2 diabetes etiology and discuss the potential therapeutic implications of targeting Rap1 in these disease areas.

Review Findings

Cardiometabolic disease characterized by obesity, glucose intolerance, dyslipidemia, and atherosclerotic cardiovascular disease remain an important cause of mortality. Evidence using mouse models of obesity and insulin resistance indicates that Rap1 deficiency increases proatherogenic PCSK9 and low-density lipoprotein cholesterol levels and predisposes these mice to develop obesity- and statin-induced hyperglycemia, which highlights Rap1’s role in cardiometabolic dysfunction. Rap1 may also contribute to cardiovascular disease through its effects on vascular wall cells involved in the atherosclerosis progression.

Summary

Rap1 activation, specifically in the liver, could be beneficial in the prevention of cardiometabolic perturbations, including type 2 diabetes, hypercholesterolemia, and atherosclerosis.

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Funding

This work was supported by an American Heart Association Transformational Project Award (971273) to L.O. and American Heart Association Research Supplement to Promote Diversity in Science (23DIVSUP1071039) to B.T.

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  1. Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA

    Heena Agarwal, Brea Tinsley, Amesh K. Sarecha & Lale Ozcan

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  1. Heena Agarwal
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H.A., B.T., A.K.S. and L.O. wrote the manuscript text. All authors reviewed the manuscript.

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Correspondence to Lale Ozcan.

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Agarwal, H., Tinsley, B., Sarecha, A.K. et al. Rap1 in the Context of PCSK9, Atherosclerosis, and Diabetes. Curr Atheroscler Rep 25, 931–937 (2023). https://doi.org/10.1007/s11883-023-01162-7

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