The role and therapeutic application of prostaglandin in ischemic renal and cardiac diseases
Date Issued
2011
Date
2011
Author(s)
Lian, Wei-Shiung
Abstract
Prostaglandin I2 (PGI2) is major prostanoids in the vascular system and a clinically proven vasodilator. The PGI2 up regulates the intracellular production of cAMP by binding to its receptor (IP), which is postulated to be responsible for the multiple effects of PGI2, such as vasodilation, antiplatelet aggregation, inhibition neutrophils and smooth muscle proliferation. In addition, the PGI2 also reported to attenuate tissue ischemia/reperfusion (I/R) injury; however, the mechanisms underlying the reported therapeutic effects are poorly understood. Therefore, this study is comprised of two parts. In the first part of studies, investigates were need to evaluate the protective roles of adiponectin (APN) in the kidney I/R injury. Results from those studies appeared that the serum concentration of APN was decreased significantly after mice had been suffering from renal ischemia reperfusion (I/R) injury. Moreover, when comparison were mode to those of control mice, it was found that several features including I/R-induced renal dysfunction (elevated serum creatinine and urea levels), inflammation (number of infiltrating neutrophils and myeloperoxidase activity), and apoptotic responses (apoptotic cell number and caspase-3 activation) etc. were all appeared to be attenuated in those of APN-treated mice. Further, molecular and biochemical analyses comfirmed that APN up-regulates heme oxygenase-1 (HO-1) via peroxisome-proliferator-activated-receptor-α (PPAR-α) dependent pathway mediated by the enhancement expression of COX-2 and 6-keto PGF1α. Chromatin immune-precipitation assay demonstrated that APN increases the binding activity of PPAR-α to the PPRE region of HO-1 promoter. Furthermore, APN induced HO-1 expression only found in wild type but not in PPAR-α gene deleted mice. This provides in vivo evidence that APN mediated HO-1 expression depends on PPARα regulation. In conclusion, this study results provide a novel APN mediated prostacyclin-PPAR-α- HO-1 signaling pathway in protecting renal I/R injury.
The second part of the investigation provides evidence for a novel mechanism that involves the secretion of paracrine cytoprotective factor(s) from bone marrow deriver-stem cells. The aim of this study attempts to explore how PGI2 synthase (PGIS) can beneficially modulate stem cell therapy, immunomudulatory, angiogenesis, and protecting the myocardium from apoptosis. This study genetically enhanced PGIS expression within mesenchymal stem cells (MSCPGIS). In vitro, the MSCPGIS did not change MSCs surface markers by flow-cytometry. In addition, the MSCPGIS could secrete 6-keto-PGF1α in a culture medium and showed decrease damage in hypoxia/re-oxygenation and H2O2 treatment. Furthermore, splenocytes proliferation was significantly suppressed under co-culture with MSCPGIS. In vivo, this study use mouse AMI model and then intra-myocardial injected 5x104 cells. Echocardiography shows improved cardiac function at 14 days post-AMI in MSCPGIS group compared to other three groups. Histological analysis on MSCPGIS treated heart demonstrated with decreased myocardial fibrosis, apoptotic cells and elevated levels on angiogenesis and cardiogenesis in the infracted region. To conclude, this study importance in explaining the role of PGIS-modified MSCs therapy in an AMI model during the early stages of disease and may have values for mediating limited process of inflammation and cardiac remodeling.
Subjects
prostacyclin
adiponectin
renal ischemia reperfusion injury
mesenchymal stem cells
myocardium infartion
paracrine factors
Type
thesis
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