title: Nilotinib attenuates endothelial dysfunction and liver damage in high-cholesterol-fed rabbits.
abstract: Nilotinib is an oral potent tyrosine kinase inhibitor that has diverse biological activities. However, its effects on hypercholesterolemia and associated disorders have not been studied yet. The present study explored the effect of nilotinib on atherosclerosis progression, endothelial dysfunction, and hyperlipidemia-associated hepatic injury in high-cholesterol (HC)-fed rabbits. Rabbits were classified into four groups: control, nilotinib, HC, and HC + nilotinib groups. Rabbits were fed either a regular diet or an HC-enriched diet for 8 weeks. By the end of the eighth week, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and in vitro analyses. Results indicated that the HC diet induced a significant elevation in the serum lipid parameters (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), lactate dehydrogenase, and nitric oxide content. Endothelial dysfunction was evident through the impairment of acetylcholine-induced relaxation of isolated aortas and the histopathological lesions of the aortic specimen. Moreover, HC significantly increased serum malondialdehyde. Liver damage was clear through increase in serum transaminases and alkaline phosphatase, and it was further supported by histopathological examination. HC increased the expression of platelet-derived growth factor receptor (PDGFR)-B in both aorta and liver tissues. Interestingly, nilotinib administration retarded atherosclerosis progression and attenuated all of the aforementioned parameters. These data suggest that nilotinib may counteract atherosclerosis development, vascular dysfunction, and hepatic damage in HC-fed rabbits through interfering with PDGF-B.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: D S
authors.initials: DS
authors.lastname: El-Agamy
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D002791:Cholesterol, Dietary / Q000008:administration & dosage* / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D006949:Hyperlipidemias / Q000188:drug therapy; D008055:Lipids / Q000097:blood; D008297:Male; D008315:Malondialdehyde; D009569:Nitric Oxide; D058226:Plaque, Atherosclerotic / Q000139:chemically induced / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D011897:Random Allocation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002791:Cholesterol, Dietary; D008055:Lipids; D011743:Pyrimidines; D009569:Nitric Oxide; D008315:Malondialdehyde; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; C498826:nilotinib
keywords: Nilotinib; PDGF; aorta; cholesterol; liver