| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 98 === Sepsis is the systemic inflammatory response with infection. Usually, septic shock is occurred at the late phase of sepsis. Septic shock is characterized by severe hypotension and reduced response to vasopressor agents, called vascular hyporeactivity. The hypotension and vascular hyporeactvity are associated with the development of multiple organs dysfunction which causes death eventually. Thus, it is important to investigate the mechanism of vascular hyporeactivity in septic shock.
Among the cell signaling pathways that are crucial to control vascular tone, Ca2+-sensitization contraction has become more and more important. The small GTP-binding protein, RhoA, plays a crucial role in mediating smooth muscle contraction. Activation of RhoA leads to inactivation of myosin light chain phosphatase via activation of Rho-kinase. The activation of RhoA is controlled by three mediators, GEF (guanine nucleotide exchange factor), GAP (GTPase activating protein) and GDI (GDP dissociation inhibitor). Among these mediators, GEF has been regarded as the most important one for RhoA activation. It has been shown that Src family tyrosine kinase (SFK) can activate RhoA via phosphorylation of GEF. In addition, it is reported that activation of PKC can lead to Ca2+-independent vasocontraction through activation of RhoA. The purpose of this study was to investigate the role of PKC and SFK in RhoA activity in thoracic aortae from endotoxemic rats.
Rats received an intravenous injection of lipopolysaccharide (LPS, 10 mg/kg) for 4 hours. After then, rats were sacrificed and the thoracic aortae were excised and immediately incubated in GF-109203X (PKC inhibitor) and PP2 (SFK inhibitor). We found that RhoA activity was decreased significantly in aortae from endotoxic rats. GF-109203X and PP2 had inhibitory effect in aortae from endotoxic rats only. In addition, the phosphorylation of SFK was decreased by GF-109203X in endotoxemic rats.
In conclusion, PKC and SFK might play a more crucial role in RhoA activation and PKC might play a more important role in activation of SFK endotoxemic rats. These results suggest that RhoA is related to vascular hyporeactivity caused by LPS-induced septic shock. In addition, PKC and SFK might be targets for improving vascular hyporeactivity.
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