P101Inorganic nitrate restores cardiac ischemic tolerance in type 2 diabetic db/db mice and protects against ischemia-reperfusion injury via an effect mediated through red blood cells

2018 ◽  
Vol 114 (suppl_1) ◽  
pp. S26-S27
Author(s):  
J N Yang ◽  
Y Tratsiakovich ◽  
A Mahdi ◽  
Z Zhou ◽  
J O Lundberg ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Reperfusion Injury ◽  
Blood Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Tolerance ◽  
Type 2 Diabetic

P6299Dietary nitrate restores cardiac ischemic tolerance in type 2 diabetic mice and protects against ischemia-reperfusion injury via soluble guanylate cyclase in red blood cells

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J N Yang ◽  
T Jiao ◽  
Y Tratsiakovich ◽  
A Mahdi ◽  
Z Zhou ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Blood Cells ◽  
Soluble Guanylate Cyclase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Tolerance ◽  
Dietary Nitrate ◽  
Nitrate Supplementation ◽  
Type 2 Diabetic

Abstract Background Inorganic nitrate has been shown to exert beneficial cardiovascular effects, which are thought to be mediated via sequential reduction of nitrate to nitrite and nitric oxide (NO). We have previously reported that hearts from type 2 diabetic db/db mice have impaired cardiac ischemic tolerance and that this effect involves reduced export of NO-like bioactivity from red blood cells (RBCs). It remains unknown whether nitrate supplementation may affect cardiac ischemic tolerance in diabetes through interference with RBC function. Purpose To test the hypothesis that dietary nitrate supplementation improves cardiac ischemic tolerance of hearts via an effect mediated through RBCs in type 2 diabetes. Methods Type 2 diabetic (db/db) and wild type (WT) mice on nitrate-free chow were treated with vehicle or nitrate (1 mM) in the drinking water for 4 weeks. Hearts were isolated and perfused using the Langendorff technique. After 30 min stabilization, the hearts were subjected to 40 min global ischemia followed by 60 min reperfusion. In protocol 1, isolated hearts from db/db and WT mice given vehicle or nitrate were perfused with buffer. In protocol 2, only hearts from untreated WT mice were used. Washed RBCs from WT or db/db mice treated with vehicle or nitrate were administered to WT hearts at the onset of ischemia with and without the soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ). In both protocols post-ischemic recovery of cardiac function was evaluated by determination of left ventricular developed pressure (LVDP). Results In Protocol 1, post-ischemic recovery of LVDP was impaired in hearts from db/db mice in comparison with hearts from WT mice (Fig. A). Dietary nitrate restored the ischemic tolerance of hearts from db/db mice but did not affect post-ischemic recovery of hearts from WT mice (Fig. A). In Protocol 2, administration of RBCs collected from vehicle-treated db/db mice significantly impaired post-ischemic recovery of hearts from WT mice (Fig. B). Notably, administration of RBCs from nitrate-treated db/db mice completely reversed the impairment of post-ischemic cardiac function induced by diabetic RBCs (Fig. B). Interestingly, post-ischemic cardiac function did not differ between hearts given RBCs from nitrate-treated db/db and WT mice (Fig. B). The protective effect of RBCs from nitrate-treated mice was abolished by pre-incubation of the RBCs with ODQ, an inhibitor of soluble guanylate cyclase (sGC) (Fig. C). By contrast, pretreatment of isolated WT hearts with ODQ failed to block the protective effect of RBCs from nitrate-treated mice (Fig C) indicating that sGC in the RBC but not in the heart is critical for nitrate-induced cardiac protection. Conclusion Dietary nitrate restores cardiac ischemic tolerance in db/db mice and protects the heart against ischemia–reperfusion injury via an RBC NO-sGC pathway.

Hydrogen sulfide attenuates lung ischemia–reperfusion injury through SIRT3-dependent regulation of mitochondrial function in type 2 diabetic rats

Surgery ◽  
2019 ◽  
Vol 165 (5) ◽  
pp. 1014-1026 ◽  
Author(s):  
Tao Jiang ◽  
Yanhong Liu ◽  
Qiuming Meng ◽  
Xiangqi Lv ◽  
Ziyong Yue ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Reperfusion Injury ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Type 2 Diabetic

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

2009 ◽  
Vol 296 (3) ◽  
pp. H719-H727 ◽  
Author(s):  
Aliaksandr A. Bulhak ◽  
Christian Jung ◽  
Claes-Göran Östenson ◽  
Jon O. Lundberg ◽  
Per-Ove Sjöquist ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
No Synthase ◽  
Ischemic Myocardium ◽  
No Production ◽  
Gk Rats ◽  
Nitrite Nitrate ◽  
Type 2 Diabetic

Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor-α (PPAR-α) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-α would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n ≥ 7) were given either 1) the PPAR-α agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor NG-nitro-l-arginine (l-NNA), 4) l-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 ± 3% and 72 ± 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 ± 3% in Wistar ( P < 0.05) and to 46 ± 5% in GK rats ( P < 0.001). The addition of either l-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 ± 5% and 65 ± 5%, respectively) and GK (IS, 66 ± 4% and 64 ± 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats ( P < 0.05). The results suggest that PPAR-α activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.

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