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Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities

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Abstract

Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating PPARγ and endothelial NOS signaling pathways. Moreover, the PPARγ-independent anti-oxidant and lipid-lowering effects of rosuvastatin might additionally play a role in the improvement of vascular endothelial function.

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Abbreviations

ACh:

Acetylcholine

SNP:

Sodium nitroprusside

ANOVA:

Analysis of variance

CPCSEA:

Committee for the purpose of control and supervision of experiments on animals

DTPA:

Diethylenetriamine pentaacetic acid

eNOS:

Endothelial nitric oxide synthase

HMG-CoA reductase:

3-Hydroxy-3-methylglutaryl-coenzyme A

L-NAME:

N(omega)-nitro-l-arginine methyl ester (L-NAME)

NBT:

Nitroblutetrazolium

NO:

Nitric oxide

PPARγ:

Peroxisome proliferator-activated receptor γ

TBARS:

Thiobarbituric acid-reactive substances

VED:

Vascular endothelial dysfunction

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Acknowledgments

We express our gratitude to Dr. Rajendar Singh Sra, M.D., Chairman, and Shri Om Parkash, Director, Rajendra Institute of Technology and Sciences, Sirsa, India, for their constant support for this study. We extend our gratitude to Mr. Sanjeev Kalra for his support during this study. We express our sincere thanks to the Indian Agricultural Research Institute for having carried out the scanning electron microscopic study.

Conflict of interest

No conflict of interest has been declared.

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Authors and Affiliations

  1. Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa, 125 055, India

    Sonam Kathuria & Pitchai Balakumar

  2. Institute of Pharmacy, Rajendra Institute of Technology, and Sciences, Sirsa, 125 055, India

    Nanjaian Mahadevan

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  1. Sonam Kathuria
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  2. Nanjaian Mahadevan
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Correspondence to Pitchai Balakumar.

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Kathuria, S., Mahadevan, N. & Balakumar, P. Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities. Mol Cell Biochem 374, 61–72 (2013). https://doi.org/10.1007/s11010-012-1505-6

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