The Cardioprotective Effect of a Statin and Cilostazol Combination: Relationship to Akt and Endothelial Nitric Oxide Synthase Activation

Manickavasagam, Saraswathy; Ye, Yumei; Lin, Yu Li; Perez‐Polo, Regino; Huang, Ming He; Lui, Charles Y.; Hughes, Michael G.; McAdoo, David J.; Uretsky, Barry F.; Birnbaum, Yochai

doi:10.1007/s10557-007-6036-0

Cited by 79 publications

(66 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mean±SEM. [4,6,20,21] . Similarly, acute pretreatment with highdose SIM (10 μmol/L) was shown to attenuate the ischemiareperfusion injury in isolated rat hearts, but chronic treatment of low-dose SIM did not [22] .…”

Section: Discussionmentioning

confidence: 99%

“…The effect of SIM on infarct size in this study is consistent with that found in previous studies because 2 mg/kg of SIM in pigs is approximately equivalent to 10 mg/kg in rats, after correction for body surface area [15] . The infarct-limitation effect of statins in ischemiareperfusion is mainly attributed to its pleiotropic effects via the PI3K/Akt/eNOS pathway because the effects of the statins can be abolished by inhibiting PI3K or eNOS [5][6][7][8][9] . In this study, we further found that acute pretreatment with single-dose SIM not only decreased the infarct size but also attenuated the no-reflow area, and we showed that the PKA pathway was another important mediator in the cardioprotection of SIM that acts by modulating the phosphorylation of eNOS at Ser 1179 and Ser 635 .…”

Section: Discussionmentioning

confidence: 99%

“…Enhancing Ser 1177/1179 phosphorylation via the PI3K/Akt pathway is considered to be the main mechanism by which statins protect against ischemia-reperfusion injury [5][6][7][8][9] . However, several lines of evidence have shown that PKA also regulates the phosphorylation of eNOS at Ser 1179 , Ser 635 , and Ser 617 in bovine eNOS (Ser 1177 , Ser 633 , and Ser 615 in humans) [24,[26][27][28][29] .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that chronic and early pretreatment with statins can improve coronary circulation and reduce the sizes of no-reflow and infarct after ischemia-reperfusion injury by enhancing endothelial (e-)nitric oxide synthase (eNOS) activ-ity through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade [4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statinmediated eNOS phosphorylation and cardioprotection. Methods: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. Results: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser 133 p-CREB protein, Ser 1179 p-eNOS, and Ser 635 p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg -1 ·min -1 ) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg -1 ) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. Conclusion: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser 1179 and Ser 635 that was partially mediated via the PKA signaling pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…However, this study found that cilostazol by itself offered no protection nor was milrinone capable of reducing the time required for ischemic preconditioning [101] . Cilostazol has recently been shown to potentiate the cardioprotective effects of low-dose atorvastatin in rats by increasing phosphorylation of eNOS [102] .…”

Section: Phosphodiesterasementioning

confidence: 99%

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Rao

2008

Acta Pharmacol Sin

View full text Add to dashboard Cite

Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

show abstract

Phosphodiesterases as Targets for Intermittent Claudication

Liu

Shakur

Kambayashi

2011

Phosphodiesterases as Drug Targets

View full text Add to dashboard Cite

Intermittent claudication (IC) is one of the most frequent forms of lower extremity peripheral arterial disease (PAD) and is most commonly caused by arterial atherosclerosis. Its clinical manifestation includes fatigue, discomfort, or pain occurring in limb muscles due to exercise-induced ischemia, thus limiting the ability of IC patients to walk and exercise. In addition to lifestyle changes (diet, exercise, and smoking cessation), pharmacological treatments are needed. Pathologically, atherosclerotic lesions cause a mismatch in oxygen supply and metabolic demand in the leg muscles during walking/exercise. This subjects the muscles to repeated ischemia and reperfusion injury that can alter structure and oxidative metabolism, resulting in insufficient utilization of oxygen supply. Despite extensive research efforts, cilostazol and pentoxifylline are the only drugs indicated for relieving the symptoms of IC, with cilostazol demonstrating significant improvement in walking distance and quality of life in these patients. Originally developed as a PDE3 inhibitor, cilostazol was later found to have several other pharmacological actions, and its success has been attributed to its multifactorial actions on platelets, endothelium, smooth muscle, and lipid profiles. Using cilostazol as an example, we discuss the rationales and pitfalls of targeting PDEs in IC, and potential strategies for the development of new and more effective pharmacological treatments.

show abstract

The Cardioprotective Effect of a Statin and Cilostazol Combination: Relationship to Akt and Endothelial Nitric Oxide Synthase Activation

Abstract: ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.

Cited by 79 publications

References 63 publications

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Phosphodiesterases as Targets for Intermittent Claudication

Contact Info

Product

Resources

About