Characterization of Protein Kinase C Alpha Deficiency in a Mouse Model ; Charakterisierung der Protein Kinase C Alpha Defizienz im Mausmodell

The protein kinase C (PKC) familiy was first described in 1977 by Nishizuka and colleagues, the pioneers in PKC research, and more than 30 years ago its role in human diseases was recognized. From that time onward, researchers worldwide endeavored to unravel regulatory functions of PKC isozymes in numerous major disorders. PKC-mediated phosphorylation of serine/threonine residues controls the activation of multiple downstream proteins. This central role in signal transduction as well as ubiquitous expression of most of the 11 PKC members makes it challenging to define the complexity of isozyme specific PKC functions. Dependent on their structure and consequent way of activation, the PKC family is classified into conventional (PKCa, PKCßI, PKCßII, PKC?), novel (PKCd, PKCe, PKC?, PKC?, PKCµ) and atypical (PKC?, PKC?/PKC?) PKC isozymes. The conventional PKCa is the most studied and best characterized isozyme, especially due to its crucial role in cancerogenesis. PKCa-evoked cellular proliferation, differentiation and apoptosis have been also proven and demonstrated in the pathogenesis of cardiovascular disorders. However, the exact role of PKCa in various pathologic conditions is still incompletely understood. The human lung disease pulmonary arterial hypertension (PAH) is characterized by progressive changes in the morphology and function of pulmonary arteries. Several PKC isozymes including PKCa are known to modulate vascular smooth muscle function. Hence, the aim of the present work was to investigate PKC isozyme specific properties in the pulmonary vasculature following stimulation with vasoactive mediators that are important in the pathogenesis of PAH. For this purpose, effects of acute hypoxia, endothelin-1 (ET-1), serotonin and the thromboxane A2 (TXA2) analog U46619 were studies in isolated perfused and ventilated mouse lungs of PKCa deficient (PKCa-/-) and corresponding wildtype (Dempsey et al.) mice. Broad spectrum PKC inhibition in WT mice was achieved with the non-selective PKC inhibitor ...