Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism.
Impaired cardiac microvascular function contributes to cardiovascular complications in diabetes. Glucagon-like peptide-1 (GLP-1) exhibits potential cardioprotective properties in addition to its glucose-lowering effect. This study was designed to evaluate the impact of GLP-1 on cardiac microvascular injury in diabetes and the underlying mechanism involved. Experimental diabetes was induced using streptozotocin in rats. Cohorts of diabetic rats received a 12-week treatment of vildagliptin (dipeptidyl peptidase-4 inhibitor) or exenatide (GLP-1 analog). Experimental diabetes attenuated cardiac function, glucose uptake, and microvascular barrier function, which were significantly improved by vildagliptin or exenatide treatment. Cardiac microvascular endothelial cells (CMECs) were isolated and cultured in normal or high glucose medium with or without GLP-1. GLP-1 decreased high-glucose-induced reactive oxygen species production and apoptotic index, as well as the levels of NADPH oxidase such as p47(phox) and gp91(phox). Furthermore, cAMP/PKA (cAMP-dependent protein kinase activity) was increased and Rho-expression was decreased in high-glucose-induced CMECs after GLP-1 treatment. In conclusion, GLP-1 could protect the cardiac microvessels against oxidative stress, apoptosis, and the resultant microvascular barrier dysfunction in diabetes, which may contribute to the improvement of cardiac function and cardiac glucose metabolism in diabetes. The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-mediated pathway.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Dongjuan
D
Wang
Peng
P
Luo
Yabin
Y
Wang
Weijie
W
Li
Chen
C
Wang
Dongdong
D
Sun
Rongqing
R
Zhang
Tao
T
Su
Xiaowei
X
Ma
Chao
C
Zeng
Haichang
H
Wang
Jun
J
Ren
Feng
F
Cao
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006943:Hyperglycemia / Q000097:blood / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects; D014688:Venoms / Q000627:therapeutic use; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000242:Cyclic AMP; D055372:AMP-Activated Protein Kinases; D020741:rho GTP-Binding Proteins