PhD defense: Jon Arne Kro Birkeland

Auditoriet i kreftsenteret, Ullevål universitetssykehus HF, Kirkeveien 166, Friday June 15, 2007 at 10:15

Dysfunctional signalling in congestive heart failure

Changes in both neuroendocrine systems and intracellular Ca2+ signalling is important in the pathogenesis of congestive heart failure (CHF). The activity in the β-adrenergic system is chronically elevated and has been shown to induce adverse effects in the heart, eg; alter the Ca2+ handling. The β-adrenergic signalling pathway regulates Ca2+ handling by phosphorylation of Ca2+ handling proteins, and a dysfunctional regulation of these proteins is probably important in CHF. Reduced activity of the Ca2+ATPase, SERCA2, which pumps Ca2+ back into the sarcoplasmatic reticulum after contraction, has been suggested as the primary cause of the altered Ca2+ handling in CHF. Recently, a serotonin mediated positive inotopic effect (PIR) has been demonstrated in left ventricular papillary muscles from failing hearts. This response might represent a maladaptive compensatory mechanism in CHF, and contribute to the dysfunctional regulation of the Ca2+ handling proteins.
In my thesis I have used a rat CHF model to investigate the cellular mechanisms behind the serotonin mediated PIR, and whether blockade of the subtype 4 of the sertonin receptor is beneficial in CHF. I have also employed a SERCA2 knock out mouse model to investigate the role of reduced SERCA2 expression in CHF.
Results from echocardiographic, papillary muscle, patch clamp, Western and quantitative real time PCR experiments showed that the PIR is mediated through the 5-HT4 receptor which regulates intracellular Ca2+ handling. The 5-HT2A receptor, which increases the myofilament Ca2+ sensitivity, also contributes to the inotropic response to serotonin. Blocking the 5-HT4 receptor was found to be beneficial in CHF suggesting that the induction of the 5-HT4 response in CHF is maladaptive. Our experiments with the SERCA2A mouse showed that sarcolemmal Ca2+ fluxes are powerfull compensatory mechanisms that can compensate for loss of SERCA2.

Prøveforelesning: Arrhytmia mechanisms in heart failure
June 14, 2007 at 16:15, Store auditorium, Ullevål universitetssykehus HF, Kirkeveien 166

Travel info

The defence takes place at Kreftsenteret at Ullevaal University Hospital.

Download map here. Kreftsenteret is located in building 11.

 

 

 

 

 

 

 

 

 

 

Webmaster Vidar, IEMF