The major cause of death among pulmonary hypertension patients is right heart failure, but the biology of right heart is not well understood. Previous studies showed that mechanisms of the activation of GATA4, a major regulator of cardiac hypertrophy, in response to pressure overload are different between left and right ventricles. In the left ventricle, aortic constriction triggers GATA4 activation via post-translational modifications without influencing GATA4 expression, while pulmonary artery banding enhances GATA4 expression in the right ventricle. We found that GATA4 expression can also be increased in the right ventricle of rats treated with chronic hypoxia to induce pulmonary hypertension, and investigated the mechanism of increased GATA4 expression. Examination of Gata4 promoter revealed that CCAAT box plays an important role in gene activation; and hypoxic pulmonary hypertension promoted the binding of CBF/NF-Y to CCAAT box in the right ventricle. We found that CBF/NF-Y forms a complex with annexin A1, which inhibits DNA binding activity. In response to hypoxic pulmonary hypertension, annexin A1 gets degraded, resulting in CBF/NF-Y-dependent activation of Gata4 gene transcription. The right ventricle contains a higher level of CBF/NF-Y compared to the left ventricle, and this may allow for efficient activation in response to annexin A1 degradation. Signaling via iron-catalyzed protein oxidation, mediates hypoxic pulmonary hypertension-induced annexin A1 degradation, Gata4 gene transcription, and right ventricular hypertrophy. These results establish a right heart-specific signaling mechanism in response to pressure overload, which involves metal-catalyzed carbonylation and degradation of annexin A1 that liberates CBF/NF-Y to activate Gata4 gene transcription.

No abstract

No abstract

Základem léčby plicní arteriální hypertenze je specifická farmakoterapie (prostanoidy, antagonisté receptorů pro endotelin, inhibitory fosfodiesterázy 5). V posledním období se ukazuje, že pacienti s těžkou formou tohoto onemocnění mají užitek z kombinační specifické léčby; tato léčba díky ovlivnění více patogenetických mechanismů dokáže opět stabilizovat časem nutně se zhoršující klinický nález tohoto závažného onemocnění. Klíčová slova: Plicní arteriální hypertenze-Specifická terapie-Kombinační specifická terapie

No abstract