Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling.
Previous studies related impaired myocardial microcirculation in diabetes to oxidative stress and endothelial dysfunction. Thus, this study was aimed to determine the effect of up-regulating pAMPK-pAKT signaling on coronary microvascular reactivity in the isolated heart of diabetic mice. We measured coronary resistance in wild-type and streptozotocin (STZ)-treated mice, during perfusion pressure changes. Glucose, insulin, and adiponectin levels in plasma and superoxide formation, NOx levels and heme oxygenase (HO) activity in myocardial tissue were determined. In addition, the expression of HO-1, 3-nitrotyrosine, pLKB1, pAMPK, pAKT, and peNOS proteins in control and diabetic hearts were measured. Coronary response to changes in perfusion pressure diverged from control in a time-dependent manner following STZ administration. The responses observed at 28 weeks of diabetes (the maximum time examined) were mimicked by L-NAME administration to control animals and were associated with a decrease in serum adiponectin and myocardial pLKB1, pAMPK, pAKT, and pGSK-3 expression. Cobalt protoporphyrin treatment to induce HO-1 expression reversed the microvascular reactivity seen in diabetes towards that of controls. Up-regulation of HO-1 was associated with an increase in adiponectin, pLKB1, pAKT, pAMPK, pGSK-3, and peNOS levels and a decrease in myocardial superoxide and 3-nitrotyrosine levels. In the present study we describe the time course of microvascular functional changes during the development of diabetes and the existence of a unique relationship between the levels of serum adiponectin, pLKB1, pAKT, and pAMPK activation in diabetic hearts. The restoration of microvascular function suggests a new therapeutic approach to even advanced cardiac microvascular derangement in diabetes.
Kusmic
Claudia
C
CNR Institute of Clinical Physiology, Pisa, Italy. kusmic@ifc.cnr.it
L'abbate
Antonio
A
Sambuceti
Gianmario
G
Drummond
George
G
Barsanti
Cristina
C
Matteucci
Marco
M
Cao
Jian
J
Piccolomini
Francesco
F
Cheng
Jennifer
J
Abraham
Nader G
NG
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005951:Glucose Tolerance Test; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin; D011524:Protoporphyrins; D013481:Superoxides; D013311:Streptozocin; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases