Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.
Highlights
Diabetes mellitus is a metabolic disease that occurs due to a deficiency of insulin production and/or action, which is characterized by a state of chronic hyperglycemia [1]
Empagliflozin and dapagliflozin prevents the tumor necrosis factor-alpha (TNFα)-mediated loss of nitric oxide (NO) bioavailability in human coronary artery endothelial cells (ECs) [71]. In this case, the sodium-glucose co-transporter 2 (SGLT2) inhibitors have no effect on endothelial NO synthase (eNOS) expression, activity, or localization, but they abolish the rise in intracellular reactive oxygen species (ROS) evoked by TNFα, suggesting that SGLT2 inhibitors elevate NO levels by interfering with the scavenging of NO by ROS
Emerging work indicate that SGLT2 inhibitors play a crucial role in promoting vascular homeostasis by regulating vascular cell function and arterial remodeling
Summary
Diabetes mellitus is a metabolic disease that occurs due to a deficiency of insulin production and/or action, which is characterized by a state of chronic hyperglycemia [1]. VSMCs possess remarkable plasticity and readily shift from a differentiated, quiescent, contractile phenotype to a synthetic phenotype that is characterized by the loss of their contractile proteins and increases in extracellular matrix synthesis, and elevated rates of proliferation and migration in response to various stimuli and environmental cues [28] This phenotypic switching allows VSMCs to participate in vascular remodeling leading to the repair of injured blood vessels, but if not properly controlled it can promote the development of occlusive vascular disease such as postangioplasty restenosis, atherosclerosis, pulmonary arterial hypertension, and aneurysm formation [29,30,31,32]. We discuss the effects of SGLT2 inhibitors on endothelial NO synthesis, vascular cell function, and arterial remodeling, and propose that the direct actions of SGLT2 inhibitors on ECs and VSMCs contribute to their favorable effects on the cardiovascular system
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