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Rhythm changes of clock genes, apoptosis-related genes and atherosclerosis-related genes in apolipoprotein E knockout mice.

ABSTRACT: BACKGROUND:Acute myocardial infarction and stroke occur more frequently in the morning, suggesting a role of the circadian clock in these main causes of death, secondary to atherosclerosis. OBJECTIVES:To investigate the expression of clock genes, apoptosis-related genes and atherosclerosis-related genes in the process of atherosclerosis. METHODS:Apolipoprotein E knockout (ApoE-/-) mice were used to establish animal models of early and advanced atherosclerosis. Real-time polymerase chain reaction, Western blotting and microarray assays were used to detect the expression of clock genes, apoptosis-related genes and atherosclerosis-related genes. RESULTS:Clock genes in ApoE-/- and C57BL/6J mouse hearts exhibited daily oscillations at the messenger RNA level. However, the expression level and rhythm between ApoE-/- and C57BL/6J mice were significantly different. Moreover, the changes became more significant as atherosclerosis developed. c-Myc and p53 genes exhibited circadian expression in C57BL/6J mice at messenger RNA and protein levels. However, the rhythm in ApoE-/- mice disappeared completely. Bcl-2 and Bax did not show daily rhythm in either strain of mouse. Aside from apoptosis-related genes, several atherosclerosis-related genes expressed time-dependent behaviour in C57BL/6J mice but not in ApoE-/- mice. CONCLUSIONS:Rhythm changes of clock genes, apoptosis-related genes and atherosclerosis-related genes may play important roles in atherosclerosis and its complications.

SUBMITTER: Xu C

PROVIDER: S-EPMC2732375 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Rhythm changes of clock genes, apoptosis-related genes and atherosclerosis-related genes in apolipoprotein E knockout mice.

Xu Chen C Lu Chao C Hua Luchun L Jin Huiming H Yin Lianhua L Chen Sifeng S Qian Ruizhe R

The Canadian journal of cardiology 20090801 8

<h4>Background</h4>Acute myocardial infarction and stroke occur more frequently in the morning, suggesting a role of the circadian clock in these main causes of death, secondary to atherosclerosis.<h4>Objectives</h4>To investigate the expression of clock genes, apoptosis-related genes and atherosclerosis-related genes in the process of atherosclerosis.<h4>Methods</h4>Apolipoprotein E knockout (ApoE-/-) mice were used to establish animal models of early and advanced atherosclerosis. Real-time pol ...[more]

PMID: 19668782

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Project description:Electronic cigarettes (e-cigarettes), also known as electronic nicotine delivery systems, are a popular alternative to conventional nicotine cigarettes, both among smokers and those who have never smoked. In spite of the widespread use of e-cigarettes and the proposed detrimental cardiac and atherosclerotic effects of nicotine, the effects of e-cigarettes on these systems are not known. In this study, we investigated the cardiovascular and cardiac effects of e-cigarettes with and without nicotine in apolipoprotein-E knockout (ApoE-/-) mice. We developed an e-cigarette exposure model that delivers nicotine in a manner similar to that of human e-cigarettes users. Using commercially available e-cigarettes, bluCig PLUS, ApoE-/- mice were exposed to saline, e-cigarette without nicotine [e-cigarette (0%)], and e-cigarette with 2.4% nicotine [e-cigarette (2.4%)] aerosol for 12 wk. Echocardiographic data show that mice treated with e-cigarette (2.4%) had decreased left ventricular fractional shortening and ejection fraction compared with e-cigarette (0%) and saline. Ventricular transcriptomic analysis revealed changes in genes associated with metabolism, circadian rhythm, and inflammation in e-cigarette (2.4%)-treated ApoE-/- mice. Transmission electron microscopy revealed that cardiomyocytes of mice treated with e-cigarette (2.4%) exhibited ultrastructural abnormalities indicative of cardiomyopathy. Additionally, we observed increased oxidative stress and mitochondrial DNA mutations in mice treated with e-cigarette (2.4%). ApoE-/- mice on e-cigarette (2.4%) had also increased atherosclerotic lesions compared with saline aerosol-treated mice. These results demonstrate adverse effects of e-cigarettes on cardiac function in mice.NEW & NOTEWORTHY The present study is the first to show that mice exposed to nicotine electronic cigarettes (e-cigarettes) have decreased cardiac fractional shortening and ejection fraction in comparison with controls. RNA-seq analysis reveals a proinflammatory phenotype induced by e-cigarettes with nicotine. We also found increased atherosclerosis in the aortic root of mice treated with e-cigarettes with nicotine. Our results show that e-cigarettes with nicotine lead to detrimental effects on the heart that should serve as a warning to e-cigarette users and agencies that regulate them.

Project description:Background and aimsAcyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is the rate-limiting enzyme catalyzing the final step of triglyceride synthesis by esterifying a diglyceride with a fatty acid. We have previously shown that apolipoprotein E-knockout (ApoE-/-) mice lacking Dgat1 have reduced intestinal cholesterol absorption and potentiated macrophage cholesterol efflux, and consequently, exhibit attenuated atherogenesis. However, hematopoietic Dgat1 deficiency lacked beneficial effects on atherosclerosis. Due to our recent results on the critical role of intestinal Dgat1 in murine cholesterol homeostasis, we delineated whether intestinal Dgat1 deficiency regulates atherogenesis in mice.MethodsWe generated intestine-specific Dgat1-/- mice on the ApoE-/- background (iDgat1-/-ApoE-/-) and determined cholesterol homeostasis and atherosclerosis development.ResultsWhen fed a Western-type diet, iDgat1-/-ApoE-/- mice exhibited a substantial decrease in fasting plasma cholesterol content in ApoB-containing lipoproteins. Although lipid absorption was delayed, iDgat1-/-ApoE-/- mice had reduced acute and fractional cholesterol absorption coupled with an elevated fecal caloric loss. In line, increased appearance of i.v. administered [³H]cholesterol in duodena and stool of iDgat1-/-ApoE-/- animals suggested potentiated cholesterol elimination. Atherosclerotic lesions were markedly smaller with beneficial alterations in plaque composition as evidenced by reduced macrophage infiltration and necrotic core size despite unaltered collagen content, indicating improved plaque stability.ConclusionsDisruption of Dgat1 activity solely in the small intestine of ApoE-/- mice strongly decreased plasma cholesterol levels by abrogating the assimilation of dietary cholesterol, partly by reduced absorption and increased excretion. Consequently, the reduced cholesterol burden significantly attenuated atherogenesis and improved the lesion phenotype in iDgat1-/-ApoE-/- mice.

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Rhythm changes of clock genes, apoptosis-related genes and atherosclerosis-related genes in apolipoprotein E knockout mice.

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Rhythm changes of clock genes, apoptosis-related genes and atherosclerosis-related genes in apolipoprotein E knockout mice.

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