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Protection of the hypoxic heart by KAPT channels and apelin

English title Protection of the hypoxic heart by KAPT channels and apelin
Applicant Baertschi Alex John
Number 120295
Funding scheme Project funding
Research institution Laboratoire moléculaire et cardiologie cellulaire Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Cardiovascular Research
Start/End 01.04.2008 - 30.09.2011
Approved amount 200'000.00
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Keywords (17)

KATP channels; Apelin; Atrium; Autocrine; Cardiac stress; Cardiomyocytes; Congenital heart disease; Forkhead transcription factors; Fox; Gene expression; Hypoxia; Metabolic sensors; Mitral insufficiency; Pediatric surgical patients; Potassium; Translation initiation; Ventricle

Lay Summary (English)

Lead
Lay summary
Background. Many patients with heart disease are subjected to considerable oxygen deficiency (hypoxia), and how the heart survives this stress is still very little known. Our studies address two critical survival mechanisms of the heart. First, certain plasma membrane channels that conduct the potassium ions (called KATP channels) can put a break on cardiac energy expenditure and oxygen consumption. We know that such channels are a complex assembly of several proteins. Our recent studies show that cardiac stress changes this assembly, increases its sensitivity to lowered oxygen levels, and may reduce the risks of heart rhythm disturbances that may otherwise arise. Second, a relatively recently discovered secretory protein called Apelin is also sensitive to cardiac stress, and helps adjust blood vessel resistance to blood flow. Our laboratory now shows that Apelin may be directed to the nucleus of Apelin-secreting cells and thereby change the proliferation and function of blood vessel muscle cells by a completely new mechanism. Interestingly, certain gene regulatory factors (called Forkhead transcription factors, or Fox) are sensitive to cardiac stress, as shown by our recent studies, and furthermore, cause expression of the KATP channels and Apelin signaling cascade. The cell mechanisms linking cardiac stress to Fox, and Fox to KATP channels and the Apelin signaling are still unknown, and are the subject of this project.Methods. With informed consent, cardiac tissue samples are obtained during heart surgery from children with congenital heart disease, and from adult patients with mitral insufficiency. The mRNA and protein expression of Fox, KATP channel subunits, and Apelin signaling molecules are quantified and related to 35 clinical parameters. This will allow for pinpointing the most important physical and chemical stressors of the heart. In parallel, cardiomyocytes and coronary muscle cells are cultured and subjected to hypoxia in cell culture while probing the involvement of several as yet unspecified stress sensors in the expression of Fox, KATP channels and Apelin signaling.Significance. Hypoxia can lead to the premature death of children and adults with heart disease, and how they survive is only partially understood. By linking chronic cardiac stress to Fox transcription factors, metabolically sensitive potassium channels, and Apelin signaling, these studies will offer new insight, and novel targets for pharmacological intervention.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
108233 Molecular physiology of atrial secretory vesicles and KATP channels in the ischemic heart 01.04.2005 Project funding

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