Der Effekt von chronisch-intermittierender Hypoxie auf myokardiale Vaskularisation, Entzündung und mitochondriale Integrität im Mausmodell

Obstructive sleep apnea syndrome (OSAS) is the most common sleep related breathing disorder and goes along with a decreased tone of the pharyngeal muscles leading to a partial or complete collapse of the upper airway during sleep which reduces the breath flow up to apnoea. It can take a minute or longer and causes a decline of the partial pressure of oxygen and oxygen saturation as well as an increase of the partial pressure of carbon dioxide. The sleep apnea is terminated by an arousal because of activation of sympathetic nervous system. The affected patients complain about daytime fatigue and show an enhanced risk for cardiovascular diseases like arterial hypertension, coronary heart disease and congestive heart failure. Considering the increasing incidence of the main risk factor obesity, prevalence of OSAS raises as well. That is the reason why we have to focus on this disease pattern and the underlying pathomechanisms. This dissertation's aim is the examination of histomorphological and molecular biological alterations of the leftventricular myocard promoting the development of cardial hypertrophy and ventricular dysfunction. We used a mouse model of chronic intermittend hypoxia (CIH) (male C57BL/6J mouses) and compared a normoxic control group KON (n=11) with a treatment group CIH (n=10). To imitate a severe OSAS, the treatment group has been exposed to a minute-by-minute change of normoxia (21% oxygen) and hypoxia (6-7% oxygen) eight hours a day for six weeks. To examine leftventricular tissue samples concerning angiogenesis, inflammation, apoptosis and mitochondrial integrity, we used (immuno-)histochemistry, qRT-PCR and electron microscopy. The angiogenic markers VEGF-A, VEGF-B, KDR and Notch1 appeared increased as a response to the insufficient oxygen supply of the tissue caused by CIH. The angiogenic signals were not followed by a significant capillary growth. They seem to be ineffective which might be caused by the CIH associated inflammation. The pro-inflammatory markers TNF-α, COX-2 and IL1-β showed a significant increase of RNA-levels as well as positive cells in immunohistochemistry. TNF-α and IL1-β are able to influence the pro-angiogenic Notch1 signaling pathway which appears cardioprotective via inhibition of fibrosis and hypertrophy. This may be one reason for the missing leftventricular hypertrophy. Another one can be the upregulation of PMCA4b which was associated with less hypertrophy and fibrosis in literature. Furthermore, the RNA-level of SOCS3 was increased, too. The protein is linked to inflammation, fibrosis and mitochondrial damage. Fitting to this, we detected a disruption of the mitochondrial integrity which might contribute to the ventricular dysfunction caused by CIH and might have a clinical impact on congestive heart failure linked to OSAS.