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The Study of the Mechanism of PARP-1 in LPS Induced Inflammation in Rat Cardiomyocyte

Author: HeFen
Tutor: BaXueQing
School: Northeast Normal University
Course: Cell Biology
Keywords: inflammatory PARP-1 NF-κB MCP-1
CLC: R363
Type: Master's thesis
Year: 2011
Downloads: 51
Quote: 0
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Abstract


Poly(ADP-ribose) polymerase-1 (PARP-1), also known as poly(ADP-ribose) transferase and poly(ADP-Ribose) synthetase is the most extensively studied and the founding member in the PARP family;PARP-1 plays a critical role in diverse cellular functions such as DNA damage detection and repair, transcriptional regulation, intracellular trafficking, chromatin modification, mitotic apparatus formation, and cell death. Although excessive activation of PARPleads to energy depletion and cell death, recent studies implicated the maligning role of PARP in a broad gamut of local or systemic inflammatory conditions.In the inflammatory response of mammals, microorganisms that invade host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. LPS/TLR4 signaling has been intensively studied in the past few years. After the stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS),TLR4 then recruits the downstream signal molecules and finally activates NF-κB, promoting the expression of other inflammatory factors,which are necessary to activate potent immune responses. NF-κB plays a pivotal role in inflammatory response。PARP-1 can act as a co-activator of NF-κB in inflammatory disorders, regulation of gene expression together. But the importance of enzymatic activity of PARP-1 in NF-κB trans-activation remains a puzzle. The study of the regulation of gene expression by PARP-1 has mainly focused on mechanisms that culminate in the control of transcription; however, a possible role of PARP-1 in the regulation of inflammatory gene expression at post-transcriptional level remains to be studied.In our studies, we investigated molecular mechanism of PARP-1 in LPS-induced inflammatory response in rat myocardial cell, including the activity change of PARP-1, the influence of PARP-1 in signaling pathway and the expression of several inflammatory factors. Our results showed that the activity of PARP-1 was up-regulate in LPS-induced inflammatory response, and regulate the transcription activity of NF-κB and expression of inflammatory factors like IL-6, MCP-1. Besides, when the activity of PARP-1 was inhibited, MCP-1 mRNA stability is highly impaired in response to LPS. Our work provided an insight into the mechanism of PARP-1 in LPS signaling pathway, and reveal the regulation of PARP-1 in the MCP-1 mRNA stability. Our study provided a new pathway to understand the mechanism of PARP-1 in inflammation, helping people find a effective way to diagnose and treat some cardiovascular diseases such as myocarditis.

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