Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice

T. Csont, Erika Bereczki, Péter Bencsik, Gabriella Fodor, A. Görbe, A. Zvara, C. Csonka, L. Puskás, M. Sántha, P. Ferdinándy

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Abstract

Objective: We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse model and to test if high cholesterol or high triglyceride is responsible for the hyperlipidemia-induced cardiac dysfunction. Methods and results: To determine the effect of cholesterol-enriched diet on cardiac performance and oxidative/nitrosative stress, wildtype and human apoB100 transgenic mice were fed a 2% cholesterol-enriched or a normal diet for 18 weeks. Serum cholesterol and LDL-cholesterol levels were significantly elevated only in the cholesterol-fed apoB100 transgenic mice, while serum triglycerides were increased in the transgenic mice fed a normal diet. Cholesterol-enriched diet significantly increased cardiac superoxide generation and NADPH oxidase expression and activity in apoB100 mice but not in wildtypes. Cardiac NO content and NO synthase activity did not change in either group. As assessed in isolated working hearts, aortic flow was significantly decreased only in apoB100 transgenic mice fed a cholesterol-enriched diet. The peroxynitrite decomposition catalyst FeTPPS attenuated the decrease in aortic flow in cholesterol-fed apoB100 mice. Immunohistochemistry showed elevated nitrotyrosine in the hearts of apoB100 mice fed the cholesterol-enriched diet. Conclusions: We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.

Original languageEnglish
Pages (from-to)100-109
Number of pages10
JournalCardiovascular Research
Volume76
Issue number1
DOIs
Publication statusPublished - Oct 1 2007

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Apolipoprotein B-100
Hypercholesterolemia
Transgenic Mice
Oxidative Stress
Cholesterol
Diet
Peroxynitrous Acid
Hyperlipidemias
Hypertriglyceridemia
Superoxides
Triglycerides
NADPH Oxidase
Serum
Nitric Oxide Synthase
LDL Cholesterol
Immunohistochemistry

Keywords

  • Cholesterol
  • Contractile function
  • Lipoproteins
  • Oxygen radicals
  • Transgenic animal models

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice",
abstract = "Objective: We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse model and to test if high cholesterol or high triglyceride is responsible for the hyperlipidemia-induced cardiac dysfunction. Methods and results: To determine the effect of cholesterol-enriched diet on cardiac performance and oxidative/nitrosative stress, wildtype and human apoB100 transgenic mice were fed a 2{\%} cholesterol-enriched or a normal diet for 18 weeks. Serum cholesterol and LDL-cholesterol levels were significantly elevated only in the cholesterol-fed apoB100 transgenic mice, while serum triglycerides were increased in the transgenic mice fed a normal diet. Cholesterol-enriched diet significantly increased cardiac superoxide generation and NADPH oxidase expression and activity in apoB100 mice but not in wildtypes. Cardiac NO content and NO synthase activity did not change in either group. As assessed in isolated working hearts, aortic flow was significantly decreased only in apoB100 transgenic mice fed a cholesterol-enriched diet. The peroxynitrite decomposition catalyst FeTPPS attenuated the decrease in aortic flow in cholesterol-fed apoB100 mice. Immunohistochemistry showed elevated nitrotyrosine in the hearts of apoB100 mice fed the cholesterol-enriched diet. Conclusions: We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.",
keywords = "Cholesterol, Contractile function, Lipoproteins, Oxygen radicals, Transgenic animal models",
author = "T. Csont and Erika Bereczki and P{\'e}ter Bencsik and Gabriella Fodor and A. G{\"o}rbe and A. Zvara and C. Csonka and L. Pusk{\'a}s and M. S{\'a}ntha and P. Ferdin{\'a}ndy",
year = "2007",
month = "10",
day = "1",
doi = "10.1016/j.cardiores.2007.06.006",
language = "English",
volume = "76",
pages = "100--109",
journal = "Cardiovascular Research",
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TY - JOUR

T1 - Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice

AU - Csont, T.

AU - Bereczki, Erika

AU - Bencsik, Péter

AU - Fodor, Gabriella

AU - Görbe, A.

AU - Zvara, A.

AU - Csonka, C.

AU - Puskás, L.

AU - Sántha, M.

AU - Ferdinándy, P.

PY - 2007/10/1

Y1 - 2007/10/1

N2 - Objective: We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse model and to test if high cholesterol or high triglyceride is responsible for the hyperlipidemia-induced cardiac dysfunction. Methods and results: To determine the effect of cholesterol-enriched diet on cardiac performance and oxidative/nitrosative stress, wildtype and human apoB100 transgenic mice were fed a 2% cholesterol-enriched or a normal diet for 18 weeks. Serum cholesterol and LDL-cholesterol levels were significantly elevated only in the cholesterol-fed apoB100 transgenic mice, while serum triglycerides were increased in the transgenic mice fed a normal diet. Cholesterol-enriched diet significantly increased cardiac superoxide generation and NADPH oxidase expression and activity in apoB100 mice but not in wildtypes. Cardiac NO content and NO synthase activity did not change in either group. As assessed in isolated working hearts, aortic flow was significantly decreased only in apoB100 transgenic mice fed a cholesterol-enriched diet. The peroxynitrite decomposition catalyst FeTPPS attenuated the decrease in aortic flow in cholesterol-fed apoB100 mice. Immunohistochemistry showed elevated nitrotyrosine in the hearts of apoB100 mice fed the cholesterol-enriched diet. Conclusions: We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.

AB - Objective: We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse model and to test if high cholesterol or high triglyceride is responsible for the hyperlipidemia-induced cardiac dysfunction. Methods and results: To determine the effect of cholesterol-enriched diet on cardiac performance and oxidative/nitrosative stress, wildtype and human apoB100 transgenic mice were fed a 2% cholesterol-enriched or a normal diet for 18 weeks. Serum cholesterol and LDL-cholesterol levels were significantly elevated only in the cholesterol-fed apoB100 transgenic mice, while serum triglycerides were increased in the transgenic mice fed a normal diet. Cholesterol-enriched diet significantly increased cardiac superoxide generation and NADPH oxidase expression and activity in apoB100 mice but not in wildtypes. Cardiac NO content and NO synthase activity did not change in either group. As assessed in isolated working hearts, aortic flow was significantly decreased only in apoB100 transgenic mice fed a cholesterol-enriched diet. The peroxynitrite decomposition catalyst FeTPPS attenuated the decrease in aortic flow in cholesterol-fed apoB100 mice. Immunohistochemistry showed elevated nitrotyrosine in the hearts of apoB100 mice fed the cholesterol-enriched diet. Conclusions: We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.

KW - Cholesterol

KW - Contractile function

KW - Lipoproteins

KW - Oxygen radicals

KW - Transgenic animal models

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U2 - 10.1016/j.cardiores.2007.06.006

DO - 10.1016/j.cardiores.2007.06.006

M3 - Article

C2 - 17658498

AN - SCOPUS:34548420672

VL - 76

SP - 100

EP - 109

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

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