Antiatherothrombotic Effects of Dipeptidyl Peptidase Inhibitors

Abstract

Atherothrombotic cardiovascular events are a leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). A number of factors beyond hyperglycemia contribute to this increased risk of cardiovascular events in T2D, including elevated blood pressure, dyslipidemia, inflammation, endothelial dysfunction, and enhanced platelet activation. Importantly, most currently available antihyperglycemic treatments for T2D do not address these additional mechanisms. Indeed, we posit that this may explain why more intensive treatment of hyperglycemia has not contributed to a reduced incidence of cardiovascular events in subjects with T2D. Incretin-targeted therapies, such as dipeptidyl peptidase 4 inhibitors, are a relatively new class of antidiabetic treatments, and preclinical as well as small mechanistic clinical studies suggest that they exert beneficial cardiovascular effects. This review focuses specifically on the potential antiatherothrombotic effects of dipeptidyl peptidase 4 inhibitors.

Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α

“…Heart sections stained with 2,3,5-triphenyltetrazolium chloride (TTC) harvested 4 days after MI revealed obvious reductions in unstained infarct areas of GLP-1(28-36)-treated hearts as compared with the scramble-or saline-treated controls ( Figure 1B). Blinded histomorphometry confirmed that pretreatment with GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) significantly decreased infarct size 4 days after MI as compared with scramble-and saline-treated controls (24.9% ± 2.4%, n = 7, vs. scramble: 32.5% ± 1.8%, n = 7; saline: 34.3% ± 2.8% n = 9; P < 0.05 for both) ( Figure 1C), with the effect of GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) treatment being comparable to that of GLP-1 (23.0% ± 1.9%, n = 13; P = NS).…”

“…Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36), a neutral endopeptidase-generated (NEPgenerated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in sAC -/cells.…”

“…However GLP-1 is rapidly degraded into the noninsulinotropic 28-amino acid metab-olite GLP-1 by ubiquitous expression of dipeptidyl peptidase 4 (DPP-4) (10). GLP-1 and GLP-1 are also cleaved by neutral endopeptidase (NEP24.11), yielding GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36), a 9-amino acid carboxy-terminal peptide with biological activity (11).…”

“…GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in sAC -/cells. We identify mitochondrial trifunctional protein-α (MTPα) as a binding partner of GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) and demonstrate that the ability of GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTPα.…”

“…NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36) is a small peptide that targets novel molecular (MTPα and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.…”