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Published on: November 10, 2017
Cardiac hypertrophy during hypercholesterolemia and its amelioration with rosuvastatin and amlodipine
Bum-Yong Kang1, Wenze Wang, Philip Palade
1Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
Insights
High cholesterol causes heart muscle growth and fibrosis in mice by increasing oxidant stress via LOX-1 and AT1R. Rosuvastatin and amlodipine treatments reversed these harmful cardiac changes.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Hypercholesterolemia is linked to atherosclerosis and cardiac hypertrophy.
- The mechanistic basis of cardiac hypertrophy in hypercholesterolemia requires further elucidation.
- Low-density lipoprotein receptor knockout (LDLR KO) mice serve as a model for hypercholesterolemia.
Purpose of the Study:
- To investigate the mechanistic basis of cardiac hypertrophy in hypercholesterolemia.
- To determine the role of LOX-1 and AT1R in hypercholesterolemia-induced cardiac changes.
- To evaluate the therapeutic potential of rosuvastatin and amlodipine in ameliorating these changes.
Main Methods:
- LDLR KO mice were fed either a regular or high cholesterol (HC) diet for 26 weeks.
- Histopathology and gene expression analysis (BNP, alpha-tubulin, TGF-β1, CTGF, LOX-1, AT1R, NADPH oxidase, NF-κB) were performed.
- Mice were also treated with rosuvastatin or amlodipine during HC diet feeding.
Main Results:
- HC diet induced cardiomyocyte hypertrophy, collagen deposition, and fibrosis in LDLR KO mice, independent of blood pressure.
- Upregulation of LOX-1, AT1R, NADPH oxidase, and NF-κB indicated increased oxidant stress.
- Rosuvastatin and amlodipine treatments reduced LOX-1, AT1R, NADPH oxidase, and NF-κB expression.
- Drug treatments significantly decreased cardiomyocyte hypertrophy and collagen deposits.
Conclusions:
- Hypercholesterolemia causes cardiac hypertrophy and fibrosis through LOX-1 and AT1R-mediated oxidant stress, independent of blood pressure.
- Rosuvastatin and amlodipine effectively ameliorate cardiac hypertrophy and fibrosis in this model.
- Targeting LOX-1 and AT1R pathways may offer therapeutic strategies for hypercholesterolemia-related cardiac dysfunction.
Abstract:
Hypercholesterolemia is a common accompaniment of atherosclerosis and may be associated with cardiac hypertrophy. To define the mechanistic basis of cardiac hypertrophy in hypercholesterolemia, we fed low-density lipoprotein receptor knockout (LDLR KO) mice regular diet or high cholesterol (HC) diet for 26 weeks. There was clear evidence of cardiomyocyte hypertrophy and collagen deposition in the hearts of LDLR KO mice fed with HC diet, confirmed by histopathology (hematoxylin and eosin and Picrosirius staining) and upregulation of genes for brain natriuretic peptide, alpha-tubulin, transforming growth factor beta1, and connective tissue growth factor (CTGF). These changes were independent of change in blood pressure. The hypercholesterolemic mice hearts showed an upregulation of LOX-1, an oxidized low-density lipoprotein receptor, and angiotensin II type 1 receptor (AT1R) at messenger RNA level. In addition, there was a marked upregulation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor kappaB (NF-kappaB) messenger RNA, indicating overexpression of markers of oxidant stress. A separate group of LDLR KO mice were fed HC diet along with a potent 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor rosuvastatin or a dihydropyridine calcium channel blocker amlodipine. Administration of rosuvastatin or amlodipine reduced the overexpression of genes for LOX-1 and AT1R and associated NADPH oxidase and NF-kappaB. These phenomena were associated with a marked decrease in cardiomyocyte hypertrophy and collagen deposits in and around the cardiomyocytes. In conclusion, this study provides evidence of cardiac hypertrophy and fibrosis in hypercholesterolemia independent of blood pressure change LOX-1 and AT1R act as possible signals for oxidant stress leading to alterations in cardiac structure during hypercholesterolemia. Most importantly, rosuvastatin and amlodipine ameliorate cardiomyocyte hypertrophy and fibrosis.
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