Rho kinase inhibitor fasudil mitigates high-cholesterol diet-induced hypercholesterolemia and vascular damage

The current study was designed to investigate the potential beneficial therapeutic outcome of Rho kinase inhibitor (fasudil) against hypercholesterolemia-induced myocardial and vascular injury in rabbits together with diet modification. Sixteen male rabbits were randomly divided into four groups: no...

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Bibliographic Details
Published in:Naunyn-Schmiedeberg's archives of pharmacology 2017-04, Vol.390 (4), p.409-422
Main Authors: Abdali, Nibrass Taher, Yaseen, Awny H., Said, Eman, Ibrahim, Tarek M.
Format: Article
Language:English
Subjects:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use
Alanine Transaminase - blood
Animals
Aorta - pathology
Aspartate Aminotransferases - blood
Atherosclerosis - drug therapy
Atherosclerosis - etiology
Atherosclerosis - metabolism
Atherosclerosis - pathology
Biomedical and Life Sciences
Biomedicine
Cholesterol - blood
Cholesterol, Dietary
Creatine Kinase - blood
Glutathione - metabolism
Hypercholesterolemia - drug therapy
Hypercholesterolemia - etiology
Hypercholesterolemia - metabolism
Hypercholesterolemia - pathology
L-Lactate Dehydrogenase - metabolism
Male
Malondialdehyde - metabolism
Myocardium - metabolism
Myocardium - pathology
Neurosciences
Nitric Oxide - metabolism
Original Article
Oxidative Stress - drug effects
Pharmacology/Toxicology
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Rabbits
rho-Associated Kinases - antagonists & inhibitors
rho-Associated Kinases - blood
Superoxide Dismutase - metabolism
Triglycerides - blood
Vascular Cell Adhesion Molecule-1 - blood
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Summary:The current study was designed to investigate the potential beneficial therapeutic outcome of Rho kinase inhibitor (fasudil) against hypercholesterolemia-induced myocardial and vascular injury in rabbits together with diet modification. Sixteen male rabbits were randomly divided into four groups: normal control group which received standard rabbit chow, hypercholesterolemic control group, and treated groups which received cholesterol-rich rabbit chow (1.5% cholesterol) for 8 weeks. Treated groups received either fasudil (100 mg/kg/day) or rosuvastatin (2.5 mg/kg/day) starting from the ninth week for further 4 weeks with interruption of the cholesterol-rich chow. Biochemical assessment of serum cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and myocardial oxidative/antioxidant biomarkers malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH), besides biochemical assessment of serum nitric oxide (NO), creatine kinase (CK), and lactate dehydrogenase (LDH) activities and serum total antioxidant capacity (TAC), was conducted. Serum vascular cell adhesion molecule 1 (VCAM-1) and serum Rho-associated protein kinase 1 (ROCK-1) were also evaluated along with histopathological examination of aorta specimens. Fasudil administration significantly decreased serum cholesterol, triglyceride (TG), and LDL and significantly increased serum HDL, with concomitant decrease in serum CK and LDH activities, NO, and restoration of serum TAC. Myocardial MDA significantly declined; SOD activity and GSH contents were restored. Serum ROCK-1 and VCAM-1 levels significantly declined as well. Vascular improvement was confirmed with histopathological examination, which revealed normal aortic intema with the absence of atheromas. Fasudil has promising anti-atherogenic activity mediated primarily via alleviation of hypercholesterolemia-induced oxidative stress and modulation of inflammatory response.
ISSN:0028-1298
1432-1912
DOI:10.1007/s00210-017-1343-x