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Review
. 2021 Mar 11:12:636267.
doi: 10.3389/fendo.2021.636267. eCollection 2021.

Aldose Reductase: An Emerging Target for Development of Interventions for Diabetic Cardiovascular Complications

Sravya Jannapureddy  1 , Mira Sharma  1 , Gautham Yepuri  1 , Ann Marie Schmidt  1 , Ravichandran Ramasamy  1
Affiliations
Review

Aldose Reductase: An Emerging Target for Development of Interventions for Diabetic Cardiovascular Complications

Sravya Jannapureddy et al. Front Endocrinol (Lausanne). .

Abstract

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.

Keywords: aldose reductase; aldose reductase inhibitor; cardiovascular diabetic complications; cardiovascular disease; diabetes; hyperglycemia; polyol pathway.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Scheme showing competition between AR and HDAC3 for the DAD of SMRT/NCOR1 and consequent transcriptional changes leading to lipid accumulation. [adapted from (128)]. AR denotes aldose reductase; DAD refers to deacetylation domain of the nuclear corepressors, SMRT refers to silencing mediator of retinoic and thyroid receptor, NCOR1 denotes nuclear corepressor 1, RAR denotes retinoic acid receptor, HDAC3 denotes histone deacetylase 3.
Figure 2
Figure 2
Scheme displays the impact of AR on changes in NAD+/NADH and consequent changes in glycolysis, mitochondrial properties and key signaling pathways leading to ischemic injury in hearts. ATP- adenosine triphosphate; JAK2- Janus activated kinase 2; MPTP-mitochondrial permeability transition pore, Akt- a serine/threonine-specific protein also known as Protein kinase B (PKB), pAkt- phosphorylated Akt, GSK3β-Glycogen synthase kinase 3 beta, STAT5- Signal transducer and activator of transcription 5.
Figure 3
Figure 3
Scheme displaying AR driven changes in NAD+/NADH and SIRT1 activity as key driver of transcription factor Egr1 acetylation and consequent induction of proinflammatory and prothrombotic genes. [adapted from (169)]. Egr1- early growth response 1, SIRT1- NAD+ dependent Sirtuin1, Ac- acetylation, NAMPT-Nicotinamide phosphoribosyltransferase, VCAM1- vascular cell adhesion molecule 1, MMPs- matrix metalloproteinases, TF-tissue factor.
See this image and copyright information in PMC

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