Lysophosphatidic Acid On Ventricular Remodeling Process In A Variety Of Cell Growth Regulators And Signal Regulatory Mechanism

Left ventricular (LV) remodeling after acute myocardial infarction (AMI), whichis characterized by infarct expansion, compensative hypertrophy of non-infarctedmyocardium and alteration of LV geometry, plays a critical role in progressive LVdysfunction and subsequent heart failure. The abnormal growth of cardiomyocytes(CM) and cardiac fibroblasts (CFB) may be account for the LV remodeling.In recent years, plant of mesenchymal stem cells (MSCs) were used in clinicaltherapy for reverse of LV remodeling. However, transplanted MSCs do not survivewell. Thereby, how to survive the MSCs in ischemia niche is required for clinicaltherapy.Lysophosphatidic acid (LPA) is a simple and natural lipid which has emerged asa potent mediator with a broad range of cellular actions, mediated viaG-protein-coupled receptor: LPA1, LPA2 and LPA3. We recently reported thatlysophosphatidic acid (LPA) may be of critical relevance in the pathophysiology ofAMI because of the significant elevation (maximal～7-fold) in serum LPAconcentration in AMI patients. However, very little is known about the effects of LPAon CM or CFB or MSCs, which are key kinds of cells in LV remodeling and therapy.In the present study, we showed that specific expressions of LPA receptorsubtypes after AMI. We study the effects of LPA on primary cultured CM and CFBand MSCs. and mechanism that LPA regulated the growth of those cells.1. AMI model was established with the ligation of anterior descending coronaryartery in SD rat. 24hr after AMI, the survivors were served as AMI group.Sham-operated group was randomly selected as control. The left ventriclefunction was deteriorated after AMI. At 48hr after AMI, there is no obviouslyhypertrophic remodelling and a remarkable cardiomyocyte apoptosis were accompanied with the notable increase of LPA3 mRNA and protein expressionsuggesting that LPA3 may concern the signal pathway of apoptosis oranti-apoptosis in early period after AMI. At 4 weeks after AMI, notable increaseof LPA1 and LPA3 expression came with obvious cardiomyocyte hypertrophyand decreased apoptosis, revealing that LPA1 and LPA3 may mainly mediate thesignal pathway of cardiomyocyte hypertrophic remodeling after AMI in rats.2. In cultured neonatal cardiomyocytes, LPA-induced hypertrophic growth wascompletely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonistOMPT, but not the LPA2 agonist Dodecylphosphate, promoted hypertrophy asexamined by 3[H]-Leucine incorporation, ANF-luciferase expression, F-actinstaining and cell area. LPA stimulated activation of PI3K/Akt and NF-κBsignaling pathway which mediated LPA-induced primary cultured ventricularcardiomyocyte hypertrophy of neonatal rats. Akt and NF-κB signaling pathwaysmay independently be implicate in LPA-stimulated myocardial hypertrophicgrowth.3. we demonstrated that LPA dose-dependently induces proliferation and collagensynthesis with maximum stimulation at 10μM that is preferentially mediated byLPA3 receptor. Interestingly, LPA also dose-dependently induced apoptotic celldeath with an IC50 of 50μM by MTT assay, hoechst staining, TUNEL and flowcytometric analysis. Moreover, apoptotic cell death may involve mitochondrialdysfunction and activation of caspase-3. Apoptosis induction of LPA may bemediated by LPA1. In addition, LPA increases the phosphorylation of ERK1/2,p38 and JNK while ERK1/2 and p38 may implicate in LPA-induced apoptosis.These data suggest that LPA exerts dual actions including both proliferation andapoptosis mediated by specific LPA receptor subtype.4. LPA protected MSCs from ischemia-induced apoptosis in dose-dependent manne which was involved in inhibition of caspase3. RT-PCR revealed that LPA1receptor expressed in MSCs and LPA1 mediated the apoptosis inhibition of LPAin MSCs since selective LPA1/LPA3 antagonist DGPP blocked the action of LPA.Moreover, LPA stimulated the activation of Akt and ERK1/2 signaling pathwaywhich exerted the protection of LPA in ischemia-induced apoptosis.In summary, our present study strongly demonstrated that LPA and its receptorsplayed important roles in LV remodeling after AMI as well as for survival oftransplanted MSCs which may be a novel target for reverse of LV remodeling andthat leading heart failure.