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Endothelial dysfunction in metabolic syndrome (insulin resistance syndrome): Role of Rho/Rho-kinase pathway and protective effect of HDL/ApoA-1

English title Endothelial dysfunction in metabolic syndrome (insulin resistance syndrome): Role of Rho/Rho-kinase pathway and protective effect of HDL/ApoA-1
Applicant Yang Zhihong
Number 105917
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Cardiovascular Research
Start/End 01.10.2004 - 31.03.2008
Approved amount 296'000.00
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Keywords (6)

endothelial function; nitric oxide; tissue factor; insulin resistance; type II diabetes mellitus; signal transduction

Lay Summary (English)

Lead
Lay summary
Clinical studies document that cardiovascular events such as unstable angina, myocardial infarction, sudden cardiac death, and thrombotic stroke do not occur randomly throughout the day but instead increase in frequency during the morning hours usually from 6 AM to noon. In addition, shift workers who have disordered daily rhythmic activity have increased incidence of cardiovascular events. It is, however, not known, whether this is primarily related to the diurnal variation of cardiovascular parameters, such as sympathetic nerve activity, blood pressure, heart rate, physical activities or directly controlled by the master clock which resides in the suprachiasmatic nuclei of the hypothalamus in mammals.Recent studies suggest an important role of the master clock gene products such as Clock and BMAL1 in the development of obesity, hypertension, and diabetes mellitus. These are risk factors for cardiovascular diseases. The aim of this study is to investigate whether there are alterations in vascular functions particularly endothelial functions using a mouse model with the mutation of another master clock gene Period2 (Per2) and whether the endothelial functional changes are associated with the metabolic cardiovascular risk factors, the phenotype observed in the CLOCK and BMAL1 mutant mice. In the present study in the frame of the SNF-research project, we showed that mice with the mutation of the clock gene (Per2) exhibit impaired endothelium-dependent relaxations due to decreased production of nitric oxide (NO), a vascular protective molecule released from endothelial NO synthase (eNOS) and a decreased production of vasodilatory prostaglandin(s) in the aorta. The endothelium-dependent relaxation is further decreased in the Per2 mutant mice during transition from the inactive (sleeping) to the active phase (awakening), whereas it is increased in the wild type littermates. Furthermore, an increase in cyclooxygenase (COX-1) protein level and COX-derived vasoconstrictor production are observed in the Per2 mutant mouse aorta. The endothelial dysfunction in the Per2 mutant mice is not associated with hypertension or dyslipidemia or diabetes mellitus. The results of this study demonstrate that mutation of the Per2 gene in mice is associated with endothelial dysfunction involving decreased production of NO and vasodilatoryprostaglandin(s) on one hand, and an increased release of COX-1-derivedvasoconstrictor(s) on the other hand, which is independent of metabolic disorders. The results suggest a potential role of the Per2 gene in maintenance of normal cardiovascular functions and may provide important clues at the molecular level for the circadian pattern of the cardiac events in the clinical settings. It may also explain the increased incidence of cardiovascular events in the shift workers.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
120435 The role of arginase II in atherogenesis, obesity and obesity-associated vascular dysfunctions 01.04.2008 Project funding (Div. I-III)

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