American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice.
Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). ⋯ PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
Antidiabetic drug pioglitazone protects the heart via activation of PPAR-gamma receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction.
The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. ⋯ Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-gamma, PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial K(ATP) channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease.
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
Activation of NF-kappaB is a critical element in the antiapoptotic effect of anesthetic preconditioning.
Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-kappaB during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-kappaB activation before I/R is unknown. ⋯ ROS-dependent activation of NF-kappaB by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-kappaB activation before I/R should protect hearts from I/R injury.
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction.
Hypoxia-induced endothelial dysfunction plays a crucial role in the pathogenesis of hypoxic pulmonary hypertension. p38 MAPK expression is increased in the pulmonary artery following hypoxic exposure. Recent evidence suggests that increased p38 MAPK activity is associated with endothelial dysfunction. However, the role of p38 MAPK activation in pulmonary artery endothelial dysfunction is not known. ⋯ Hypoxia exposure increased superoxide generation and p38 MAPK expression. The inhibition of p38 MAPK restored endothelium-dependent relaxation, increased bioavailable NO, and reduced superoxide production. In conclusion, the pharmacological inhibition of p38 MAPK was effective in increasing NO generation, reducing superoxide burden, and restoring hypoxia-induced endothelial dysfunction in rats with hypoxia-induced pulmonary hypertension. p38 MAPK may be a novel target for the treatment of pulmonary hypertension.
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
Contribution of nerve growth factor to augmented TRPV1 responses of muscle sensory neurons by femoral artery occlusion.
In rats, hindlimb muscle ischemia induced by femoral artery occlusion augments the sympathetic nervous response to stimulation of transient receptor potential vanilloid type 1 (TRPV1) by injection of capsaicin into the arterial blood supply of the hindlimb muscles. The enhanced sympathetic response is due to alterations in TRPV1 receptor expression and its responsiveness in sensory neurons. The underlying mechanism by which TRPV1 receptor responses are increased after muscle vascular insufficiency/ischemia is unclear. ⋯ With the addition of NGF in the culture dish containing the DRG neurons, the magnitude of the DRG neuron response to capsaicin was greater (6.4 +/- 0.27 nA; P < 0.05 vs. control) than that seen in control (2.9 +/- 0.16 nA). Note that this NGF effect was seen in isolectin B(4)-negative DRG neurons, a group of thin fiber nerves that contain neuropeptides and depend on NGF for survival. These data suggest that NGF affects a selective subpopulation of the afferent neurons in mediating augmented TRPV1 responses after femoral artery occlusion.