| It is well known that cardiac myocyte(MC) hypertrophy induced by a variety of bioactive agents(mainly Angll, NE, ET-1) is considered as an abnormal excessive growth of MC. Meanwhile, Overexpression of inflammatory cytokine TNF-α(a potent inducer of MC apoptosis) in MC is a key step for progression of heart failure(HF). Therefore, to investigate the cellular mechanisms responsible for controlling and regulating the growth and TNF-a production in MC might be helpful to clarify the pathogenesis and to develop new intervention methods for prevention-treatment of myocardial hypertrophy(MH) and HERecently, a variety of studies have indicated that MAPKs and PPARs(two isoforms -a and -y) play an important role in regulation of cell biological process and secretion function. MAPKs are the cytoplasmic signaling molecular family that can converge and transduct extracellular signals into cell nucleus for mediating the cell biological responses such as growth and proliferation(by the subfamily p44/p42 MAPK) and apoptosis(by p38MAPK). PPAR-KX/-Y, belonging to type II nuclear receptor subfamily, are ligand-dependent transcription factors. It has recently been demonstrated that PPAR-@/-γ play an important role in regulating the inflammatory response in macrophages and proliferation in vascular smooth muscle cells. But the effects of p44/p42MAPK and PPAR-α/-γ on MH and HF are still unclear. Thus, in this study, we designed (1)﹖o use MC protein synthesis rate(3H-leucine incorporation assay), total protein content, cell diameter and/or c-fos mRNA and c-myc mRNA abundance(by Northern blot method) as the indexes of cell growth state. (2)to study the effects of activation and deactivation of p44/p42MAPK and PPAR-α/-γ on Angll and NE-induced MC hypertrophic responses and/or on LPS-induced MC TNF-α production. (3)to clarify the pathogenesis in progression of MH and HF, and to provide new targets and develop effective agents to prevent and treat MH and HF.This study consists of 4 parts, results in each part as follows: (1)Treatment ofMC with AngII(10nmol/L) and NE(1μmol/L) resulted in elevation of growth index (considered as hypertrophic response, HR), activation of p44/p42MAPK (assayed by phospho-p44/p42MAPK protein content, Western blot method). When the activation of p44/p42MAPK was blocked by using U0126(a MEK-MAPK pathway blocker), both the Angll-induced and NE-induced HR were inhibited. On the other hand, the receptor-signal transduction pathway for Angll or ME to activate p44/p42MAPK is quite different, suggesting that p44/p42MAPK is the common signaling pathway for HR induced by both Angll and NE. (2)Angll-induced activation of p44/p42MAPK, HR and upregulation of c-fos mRNA and c-myc mRNA were all inhibited by transfection of MC with antisense oligodeoxynucleotide(ODN) to p44/p42MAPK. (3)There was no basal TNF-α production from MC. Incubation MC with LPS(a potent agent causing acute HF), TNF-α production (assayed by ELISA method) increased significantly. (4)both the Angll- and NE-induced HR as well as LPS-induced TNF-α production were inhibited after activation of PPAR-a or -y by corresponding ligands.In conclusion, the present study demonstrates that (1)activation of p44/p42MAPK is the most important signaling mechanism for progression of MC hypertrophic response, (2)activation of PPAR-o/-y functions as a negative regulator for the MC hypertrophic response as well as TNF-a production, (3)antisense ODN to p44/p42MAPK and PPAR-o/-y activators(such as lipid modulator and insulin sensitizer) may exert direct anti-hypertrophy and anti-HF effects, (4)effect of PPARs on MH and HF and their underlying mechanisms need further investigation.
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