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Fig. 2 | Cardiovascular Diabetology

Fig. 2

From: The role of dipeptidylpeptidase-4 inhibitors in management of cardiovascular disease in diabetes; focus on linagliptin

Fig. 2

Cellular and molecular mechanisms of linagliptin mediated cardiovascular protection. The schematic depicts deleterious effects of excess nutrient consumption/obesity in the development of cardiometabolic syndrome and T2DM leading to vascular injury, stiffening and cardiovascular dysfunction. Circles with letters A through F indicate targets of LGT-mediated CV protection due to LGT modulation of key pathophysiological events. a The classical effects of LGT through inhibition of DPP-4 leading to increased levels of GLP-1 incretin results in GLP-1-mediated cell signaling cascade implicated in improved endothelial function and endothelial regulation of other vascular cells and cardiomyocytes. b In addition to cell-specific effects, the glycemic control by GLP-1 incretin signaling contributes to CV health by suppressing deleterious effects of hyperglycemia directly and amelioration of CV injury by AGE/RAGE signaling. The mechanisms largely involve oxidative stress mediated by both NADPH oxidase-dependent, as well as, mitochondrial generated oxidative stress. The enhanced oxidative stress, in turn, contributes to impairment in two key cellular events comprising decrease in bioavailable NO and upregulation of a proinflammatory response. c The GLP-1-independent mechanisms of LGT include modulation of cytokine imbalance, RAAS activation, potentiation of SDF-1α signaling to NO, improvement in insulin signaling and suppression of dyslipidemic effects on vasculature. d As DPP-4 is expressed in immune cells and mounts a pro-inflammatory response through macrophage and lymphocyte polarization, LGT is an effective suppressor of maladaptive immune/inflammatory response. e The recent studies demonstrating LGT-mediated decrease in the levels of TRAF3IP2, which is a key modulator of inflammatory and pro-fibrotic responses in the WD-fed heart, provides novel insight into the effects of LGT in improving CV dysfunction in obesity cardiomyopathy. f Recent studies indicate that linagliptin prevents WD-induced deficiency of the anti-aging protein, klotho, in the aorta of WD fed female mice and that the salutary effects of linagliptin on klotho involve increased bioavailable NO. Taken together, the multiple cellular mechanisms of LGT may be contributing to the beneficial effects of LGT observed in pre-clinical models of obesity and diabetes, as well as, small clinical trials showing CV protection in stroke, myocardial infarction and nephropathy. AC adenylate cyclase, AGE advanced glycation end products, AP-1 activator protein-1, AT1R angiotensin type 1 receptor, AMPK AMP-activated protein kinase, AKT protein kinase-B, Ang II angiotensin 2, Aldo aldosterone, p-CREB phospho-cyclic AMP response element binding, EC endothelial cell, ET-1 endothelin-1, ERK extracellur signal-regulated kinase, eNOS endothelial nitric oxide synthase, FGFR fibroblast growth factor receptor, GLP-1 glucagon-like peptide-1, GLP-1R GLP-1 receptor, HO-1 hemoxygenase-1, IL-6 interleukin-6, LGT linagliptin, MCP-1 monocyte chemoattractant protein-1, MMP-2 matrix metalloproteinase-2, MR mineralocorticoid receptor, NF-κB nuclear factor-kappa B, PI3K phosphoinositide 3-kinase, RAGE receptor for AGE, ROS reactive oxygen species, S6K1 ribosomal protein S6 kinase 1, TGF-β transforming growth factor-1, TRAF3IP2 TRAF3 interacting protein 2, mTOR mechanistic target of rapamycin

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