Cardiovascular pharmacologyRosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: Role of iNOS and VEGF☆
Introduction
Cardiovascular diseases account for high number of deaths all over the world. Myocardial infarction is the common presentation of cardiovascular disease (Patel et al., 2010). After myocardial ischemia, the heart cells die and collagen deposition ensues in its place (Krijnen et al., 2002). Angiogenesis is defined as the formation of new blood vessels from the preexisting ones. Angiogenesis may be beneficial in some pathologic conditions, such as in ischemic diseases (Iglarz et al., 2001). Ischemia-induced angiogenesis takes place as a compensatory mechanism to provide blood supply to ischemic tissues and preserves blood flow in ischemic heart or leg (Heil and Schaper, 2004).
Therapeutic angiogenesis is a new strategy that has been emerged to treat tissue ischemia by promoting the proliferation of collateral vessels. This strategy received great attention as a promising therapy developed in ischemic diseases (Freedman and Isner, 2001). In ischemic tissues, hypoxia-induced angiogenesis takes place due to the increase in expression of some important growth factors, such as vascular endothelial growth factor (VEGF) (Lee et al., 2000). Indeed, NO has been reported to be an important mediator in the cardiovascular system and is thought to be critical in signal transduction through the ischemic myocardium (Xi et al., 1999). Nitric oxide is generated by nitric oxide synthase (NOS) enzyme. Inducible nitric oxide synthase (iNOS) isoform has been reported to play an important role in reducing the infarct size during myocardial infarction (Shah and Wainwright, 2000). It has been demonstrated that iNOS and VEGF are over expressed and promote tumor angiogenesis and metastasis (Chen et al., 2009). In addition, iNOS-derived NO was reported to promote survival of ischemic tissue by stimulating angiogenesis (Kane et al., 2001).
Some clinical trials established the benefits of statins on coronary heart diseases and strokes (Heart Protection Study Collaborative Group, 2003, Law et al., 2003), ischemic cerebrovascular events (Greisenegger et al., 2004) and hind limb ischemic tissues (Sata et al., 2001). Statins were reported to improve the endothelial function by mechanisms that are unrelated to the cholesterol lowering effect. Some of these mechanisms involve prevention of inflammation, down regulation of the systemic inflammatory response (Liu et al., 2009) and induction of angiogenesis (Hamelin and Turgeon, 1998).
Based on the previous demonstration for the cardio protective role of statins in ischemic myocardium, this study investigated one putative mechanism that might contribute to this beneficial effect. Focusing on the angiogenic role, the present study was designed to examine the pro-angiogenic effect of rosuvastatin in myocardial infarct rats.
Section snippets
Experimental animals
Male adult Wistar rats (200–250 g) were used in the present study. Rats were maintained in groups of five in stainless steel cages under controlled laboratory conditions (23–28 °C and normal dark/light cycle). Rats were acclimatized to the experiment conditions for seven days before starting the experiment. Water and food were provided ad libitum. All animal care and experimental procedures were approved by the Institutional Laboratory Animal Care and Use Committee at Faculty of Pharmacy, Suez
Effect of treatment with rosuvastatin on percentage survival and ECG pattern
In the present study, isoproterenol (85 mg/kg/24 h, s.c.) was administered to induce acute myocardial infarction in rats. Injection of isoproterenol resulted in a decrease in the percentage of surviving rats (75%) after the first week of injection compared to (62.5%) after 9 weeks of injection versus a surviving percentage equals 100% in saline-treated rats. Treatment with rosuvastatin did not significantly modify the number of surviving rats compared to isoproterenol (week 9) group (Table 1).
Discussion
The current study was the first to investigate the pro-angiogenic effect of rosuvastatin in experimentally-induced acute myocardial infarction in rats. In the present study, acute injection with isoproterenol induced myocardial fibrosis and necrosis. Evaluation of myocardial fibrosis at week 9 highlighted a non significant decrease in fibrosis grades compared to those recorded at the end of week 1, indicating a slow rate of recovery from damage induced by isoproterenol. The present results
Sources of support
The authors did not receive a fund from any organization.
Acknowledgments
The authors wish to acknowledge the generous gift of rosuvastatin from Al-Hekma Pharmaceutical Co. (6th of October City, Egypt).
References (59)
- et al.
Chronic oral administration of raw garlic protects against isoproterenol-induced myocardial necrosis in rat
Comp. Biochem. Physiol. C: Pharmacol. Toxicol. Endocrinol.
(2003) - et al.
Therapeutic angiogenesis for ischemic cardiovascular disease
J. Mol. Cell Cardiol.
(2001) - et al.
Combined atorvastatin and coenzyme Q10 improve the left ventricular function in isoproterenol-induced heart failure in rat
Eur. J. Pharmacol.
(2011) - et al.
Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats
Am. J. Pathol.
(2007) - et al.
Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events
J. Neurol. Sci.
(2004) - et al.
Hydrophilicity/lipophilicity, relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors
Trends Pharmacol. Sci.
(1998) VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR)
Biochem. Biophys. Res. Commun.
(1998)- et al.
Nitric oxide inhibits migration of cultured endothelial cells
Biochem. Biophys. Res. Commun.
(1996) - et al.
Regulators of angiogenesis and strategies for their therapeutic manipulation
Int. J. Biochem. Cell Biol.
(2006) - et al.
Cardioprotective effect of melatonin against isoproterenol induced myocardial infarction in rats, a biochemical, electrocardiographic and histoarchitectural evaluation
Eur. J. Pharmacol.
(2010)
Paracrine and autocrine effects of nitric oxide on myocardial function
Pharmacol. Therapeut.
Simvastatin attenuates cardiopulmonary bypass-induced myocardial inflammatory injury in rats by activating peroxisome proliferator-activated receptor γ
Eur. J. Pharmacol.
Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis
Circ. Res.
Optimal conditions and comparison of lactate dehydrogenase catalysis of the lactate-to-pyruvate and pyruvate-to-lactate reactions in human serum at 25, 30, and 37 degrees C.
Clin. Chem.
Expression of inducible nitric oxide synthase and vascular endothelial growth factor in ameloblastoma
J. Craniofac. Surg.
Constitutive and inducible nitric oxide synthase, role in angiogenesis
Antioxid. Redox Signaling
Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells
Thromb. Vasc. Biol.
Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability
Proc. Nat. Acad. Sci. U.S.A.
Mechanisms of vascular preservation by a novel NO donor following rat carotid artery intimal injury
Am. J. Physiol.
MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes, a randomised placebo-controlled trial
Lancet
Influence of mechanical, cellular and molecular factors on collateral artery growth (arteriogenesis)
Circ. Res.
Chronic blockade of endothelin receptors improves ischemia-induced angiogenesis in rat hindlimbs through activation of vascular endothelial growth factor–NO pathway
Arterioscler. Thromb. Vasc. Biol.
Pravastatin attenuates allergic airway inflammation by suppressing antigen sensitization, interleukin 17 production and antigen presentation in the lung
Thorax
Structural mechanism for statin inhibition of HMGCoA reductase
Science
Inducible nitric oxide synthase (iNOS) activity promotes ischemic skin flap survival
Br. J. Pharmacol.
Ellagic acid ameliorates isoproterenol induced oxidative stress, evidence from electrocardiological, biochemical and histological study
Eur. J. Pharmacol.
ECG findings in normal rats and after administration of isoproterenol. Ind
J. Physiol. Pharmacol.
Apoptosis in myocardial ischemia and infarction
J. Clin. Pathol.
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This work has been done at the Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.