Nilotinib attenuates endothelial dysfunction and liver damage in high-cholesterol-fed rabbits
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1Department 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.
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.
Insights
Nilotinib, a tyrosine kinase inhibitor, was studied in high-cholesterol fed rabbits. It significantly reduced atherosclerosis, endothelial dysfunction, and liver injury, suggesting a protective role against these conditions.
Area of Science:
- Pharmacology
- Cardiovascular Biology
- Hepatology
Background:
- Hypercholesterolemia and its associated disorders like atherosclerosis, endothelial dysfunction, and liver injury remain significant health concerns.
- The therapeutic potential of tyrosine kinase inhibitors, such as nilotinib, beyond their known biological activities is not fully understood.
- Nilotinib's effects on hypercholesterolemia and related pathologies have not been previously investigated.
Purpose of the Study:
- To investigate the impact of nilotinib on atherosclerosis progression in a rabbit model of high-cholesterol diet.
- To evaluate nilotinib's efficacy in mitigating endothelial dysfunction and hyperlipidemia-induced hepatic injury.
- To explore the potential role of platelet-derived growth factor receptor-B (PDGFR-B) in nilotinib's protective effects.
Main Methods:
- Rabbits were fed a high-cholesterol (HC) diet for 8 weeks, with or without nilotinib administration.
- Biochemical analyses measured serum lipid profiles, liver enzymes, and oxidative stress markers.
- Histological and immunohistochemical analyses assessed aortic and liver tissues, alongside in vitro functional assays for endothelial function.
Main Results:
- The HC diet significantly elevated serum lipids, lactate dehydrogenase, nitric oxide, and malondialdehyde, alongside causing endothelial dysfunction and liver damage.
- HC feeding increased PDGFR-B expression in the aorta and liver.
- Nilotinib treatment markedly attenuated these adverse effects, reducing atherosclerosis, improving endothelial function, and protecting against liver injury.
Conclusions:
- Nilotinib demonstrates significant protective effects against diet-induced atherosclerosis, endothelial dysfunction, and hepatic damage in rabbits.
- These benefits may be mediated through the inhibition of PDGFR-B signaling pathways.
- Nilotinib presents a potential therapeutic strategy for managing hypercholesterolemia-associated cardiovascular and hepatic complications.
