Mechanism of cGMP-mediated protection in a cellular model of myocardial reperfusion injury

Abdallah, Yaser; Gkatzoflia, Anna; Pieper, Heinz P.; Zoga, E.; Walther, S. C.; Kasseckert, Sascha; Schäfer, Matthias; Schlüter, K.-D.; Piper, Hans Michael; Schäfer, Claudia

doi:10.1016/j.cardiores.2005.01.007

Cited by 68 publications

(56 citation statements)

References 24 publications

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“…It is noteworthy, however, that the magnitude of the LDH release in hearts perfused under normoxia is marginal compared to that observed following reperfusion after ischemia or anoxia [62]. The cGMP-dependent reduction of LDH release may be independent of the aforementioned metabolic effects, since cGMP prevents cell death by combined effects on the mitochondrial transition pore, intracellular calcium regulation and stress-activated signaling [47,63,64]. Alternatively, increased availability of cytosolic glycolytically-derived ATP might improve ionic homeostasis, as multiple membrane-associated channels preferentially use glycolyticallyderived ATP [65][66][67][68][69], and thus contribute in this fashion to improved membrane integrity.…”

Section: Discussionmentioning

confidence: 96%

Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation

Khairallah

Gélinas

et al. 2008

Journal of Molecular and Cellular Cardiology

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While the balance between carbohydrates and fatty acids for energy production appears to be crucial for cardiac homeostasis, much remains to be learned about the molecular mechanisms underlying this relationship. Given the reported benefits of cGMP signaling on the myocardium, we investigated the impact of its chronic activation on cardiac energy metabolism using mice overexpressing a constitutively active cytoplasmic guanylate cyclase (GC +/0 ) in cardiomyocytes. Ex vivo working GC +/0 heart perfusions with 13 C-labeled substrates revealed an altered pattern of exogenous substrate fuel selection compared to controls, namely a 38±9% lower contribution of exogenous fatty acids to acetyl-CoA formation, while that of carbohydrates remains unchanged despite a two-fold increase in glycolysis. The lower contribution of exogenous fatty acids to energy production is not associated with changes in energy demand or supply (contractile function, oxygen consumption, tissue acetyl-CoA or CoA levels, citric acid cycle flux rate) or in the regulation of β-oxidation (acetyl-CoA carboxylase activity, tissue malonyl-CoA levels).However, GC +/0 hearts show a two-fold increase in the incorporation of exogenous oleate into triglycerides. Furthermore, the following molecular data are consistent with a concomitant increase in triglyceride hydrolysis: (i) increased abundance of hormone sensitive lipase (HSL) protein (24±11%) and mRNA (22±4%) as well as (ii) several phosphorylation events related to HSL inhibitory (AMPK) and activation (ERK 1/2) sites, which should contribute to enhance its activity. These changes in exogenous fatty acid trafficking in GC +/0 hearts appear to be functionally relevant, as demonstrated by their resistance to fasting-induced triglyceride accumulation. While the documented metabolic profile of GC +/0 mouse hearts is partly reminiscent of hypertrophied hearts, the observed changes in lipid trafficking have not been

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Section: Discussionmentioning

confidence: 96%

Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation

Khairallah

Gélinas

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…In these studies, the protective effect of PKGI-α was not inhibited by HMR1098, the selective blocker of sarcolemmal K ATP channel thereby further supporting the role of mitoK ATP channels in PKG-dependent protection. Also, it has been shown that cGMP-dependent signals activate sarcoplasmic reticulum Ca 2+ pump (SERCA) via PKG-dependent phosphorylation of phospholamban (29). The increase in SERCA activity reduces peak intracellular Ca 2+ as well as its oscillation during reoxygenation attenuates the excessive activation of the contractile machinery and thereby prevents hypercontracture.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial KATP channels when administered at reperfusion following ischemia in rabbits

Salloum

Takenoshita

Ockaili

et al. 2007

Journal of Molecular and Cellular Cardiology

123

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Phosphodiesterase-5 (PDE-5) inhibitors including sildenafil and vardenafil induce powerful preconditioning-like cardioprotective effect against ischemia/reperfusion injury through opening of mitochondrial K ATP channels in the heart. The goal of these studies was to demonstrate the protective effect of sildenafil and vardenafil on reperfusion injury and to compare it with the antianginal vasodilator nitroglycerin (NTG). In addition, we determined the role of mitochondrial K ATP channels in protection. Adult male New Zealand white rabbits were anesthetized and subjected to ischemia by 30 min of coronary artery occlusion followed by 3 hrs of reperfusion. Seven groups were studied. 1-Controls; 2-Sildenafil (total dose: 0.71 mg/kg; iv) infused for 65 min starting 5 min before reperfusion; 3-Sildenafil+5-hydroxydecanoate (5-HD, blocker of mitochondrial K ATP channel, total dose: 5 mg/kg) administered as 2 bolus injections; 4-Vardenafil (total dose: 0.014 mg/kg; iv) administered as in group 2; 5-Vardenafil+5-HD administered as in group 3; 6-5-HD administered as two bolus injections and 7-Nitroglycerin (NTG, total dose: 2 μg.kg -1.min -1) administered as in group 2. Infarct size was reduced in sildenafil (19.19±1.3%) as well as vardenafil (17.0±2.0%) treated groups as compared to controls (33.8 ± 1.7%). However, NTG failed to confer similar cardioprotection (31.5±0.8%). 5-HD blocked the cardioprotective effects of sildenafil and vardenafil as shown by an increase in infarct size (34.0 ±1.1% and 28.3±1.9%, respectively). Both sildenafil and vardenafil protect the ischemic myocardium against reperfusion injury through a mechanism dependent on mitochondrial K ATP channel opening. Future clinical trials are needed to exploit the potential utility of PDE-5 inhibitors in cardioprotection in patients with coronary artery disease.

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“…To further investigate whether protection could be conferred in the db/db mouse, we next analyzed the upstream signaling molecule NO ⅐ . Current dogma (1,10,19,21,25) suggests that the NO/cGMP pathway is prominent in NO ⅐ -mediated protection against MI/R injury. Delivery of the NO ⅐ donor DPTA 5 min before reperfusion yielded significant protection in both nondiabetic and diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway

Elrod¹,

Greer²,

Lefer³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Mechanism of cGMP-mediated protection in a cellular model of myocardial reperfusion injury

Cited by 68 publications

References 24 publications

Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation

Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation

Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial KATP channels when administered at reperfusion following ischemia in rabbits

Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway

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