| Summary: | 碩士 === 高雄醫學大學 === 藥理學研究所 === 99 === Heat shock proteins (HSP) had been regarded as only with intracellular functions. Recent studies suggest that they can also be released to extracellular space and have physiologic functions. Given the facts that there are elevated plasma HSP levels in patients with septic shock, however, the role of extracellular HSP (eHSP) in the mechanisms in septic cardiomyopathy is still unknown. We therefore further investigated the role of eHSP in the pathogenesis of septic cardiomyopathy.
In the animal model of septic cardiomyopathy, we anesthetized the Wistar rats and injected lipopolysaccharide (LPS). Then the hemodynamic changes were monitored via catheters through femoral artery and catheters into the left ventricle via the carotid artery.
We found that intravenous injection of LPS induced a profound myocardial depression indicated by decreased mean arterial pressure, left ventricular systolic pressure, Max dp/dt and Min dp/dt, with compensatory increase of heart rates. In addition, plasma levels of TNF-α, nitric oxide, GOT/GPT, uric acid and LDH were increased but the plasma level of glucose was decreased. The protein levels of iNOS, COX-2, ERK1/2, p38, IκBα, p65 and MMP-9 were increased by LPS in heart and liver tissue.
However, these changes were significantly attenuated when HSP73 recombinant protein (rHSP73; 20 μg/kg, iv) were injected 10 minutes before LPS injection. Our results showed that after pretreatment with rHSP73, the myocardial suppression was attenuated with higher mean blood pressure, left ventricular systolic pressure and Max dp/dt and Min dp/dt. In addition, the increased plasma levels of TNF-α, NO, GOT/GPT, glucose, UA and LDH induced by LPS were suppressed by rHSP73, and the increased protein levels of iNOS, COX-2, ERK1/2, p38, IκBα, p65 and MMP-9 were also suppressed by rHSP73.
In conclusion, we found that rHSP73 inhibited LPS-induced myocardial dysfunction through suppression of cytokine production such as TNF-α and expression of iNOS and COX-2. This effect might mediated by the inhibition of MAPK and IκBα/NF-κB signaling pathway. It’s also down-regulated the plasma level of NO, and the protein and activation level of MMP-9. Taken together, these results indicate that eHSP has both anti-inflammatory effects and cardioprotective effects in septic cardiomyopathy.
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