| BackgroundMetabolic syndrome(MS) is not a specific disease but a clinical syndrome consisting of a variety of metabolic disorders of which insulin resistance(IR) is acknowledged as the key characteristic. MS includes obesity,hypertension,type2diabetes and hyperlipidemia and so on. For the patients with MS, ventricular remodeling is a crucial risk factor for related cardiovascular events and death.MS as well as its components will finally comprimise the structure and function of the heart,and ventricular remodeling is the earliest and the most considerable lpathological change. Numerous factors including TGF-β1,COL-I,COL-III would be implicated in pathogenesis of ventricular remodeling. PPARs are a superfamily of transcription factors activated by ligands of which PPAR-a and PPAR-y have been demonstrated to be related with the development of MS. Fenofibrate (FEN), a PPAR-a agonist, can decrease circulating FFA and TG levels and increase HDL-C level as well as improve IR by promoting fatty acid metabolism.Furthermore, Pioglitazone(PIO), a PPAR-y agonist, can significantly improve IR, lower blood sugar and FFA levels by promoting glucose utilization in peripheral tissues and fat metabolism. Besides, PIO helps to control blood pressure. FEN and PIO can also inhibit the expressions of TGF-β1, COL-Ⅰ and COL-III to inhibit ventricular remodeling. ObjectiveThis study is to explore the effect and mechanism of PPAR-a or y agonist alone or in combination on MS-associated ventricular remodeling by clinical studies and animal experiments, which is to explore a new alternative regimen for preventing MS-associated ventricular remodeling.Methods(1) Clinical study:256MS patients were randomly divided into4groups:treatment group(basic treatment,BT group,n=64),fenofibrate group(FEN group,n=65),pioglitazone group(PIO group,n=63), and fenofibrate+pioglitazone group(FEN+PIO group,n=64).30healthy subjests were recruited as normal control group.All patients were received basic treatment. Furthermore, the patiens were treated with fenofibrate in FEN group, pioglitazone in PIO group, and both agents in FEN+PIO groupAfter24weeks, the changes and correlation of the following index, including blood pressure,blood sugar, blood lipids,TGF-β1,PICP, PIIINP and MMP-9, were analyzed in these groups. Additionally, the change of left ventricular structure parameters were obtained by using color ultrasound.(2) Establishing of rat MS models:SD rats were fed with60%fructose diet for MS models. Rat’s weight, blood pressure, FBS, FINS were tested regularly during period of construction model.(3) Animal experiment:After establishing of rat MS models, all MS animals were randomly divided into4groups:model control group (MC group,n=10), fenofibrate (FEN group, n=11), pioglitazone group (PIO group, n=10) and fenofibrate+pioglitazone group (FEN+PIO group, n=11). Normal SD rats without MS were fed with standard diet that were included as the control group (NC group, n=6). The rats in each group were received different interventions as above stated, and the following measurements were regularly obtained including weight, blood pressure (BP), blood glucose, blood lipids as well as liver and kidney function. After4weeks, all animals were sacrificed and then these index were measured including myocardial structure, mRNA and protein expressions of PPAR-a and PPAR-y, and circulated levels of TGF-β1, Smad3, COL-I and COL-III levels. The differences and relationships among the above index in each group were analyzed.Results(1) Clinical studie1) Compared with NC group:The levels of these index were significantly increased in BT group including BP, FBS, FINS, HOMA-IR, TC, LDL-C, TG, FFA, ALT, UA, TGF-β1, PCIP, PIIINP and MMP-9(P<0.01or P<0.05).2) Compared with BT group:the levels of TG, FFA and FINS were decreased in FEN group(P<0.05); the levels of TG, FFA, HbA1c, FINS, TGF-β1, PICP, PIIINP and MMP-9as well as HOMA-IR weredecreased in PIO group(P<0.01or P<0.05); the levels of TQ FFA, HbA1c, FINS, TGF-β1, PICP, PIIINP, MMP-9, DBP, HOMA-IR, LVM and LVMI were decreased in FEN+PIO group(P<0.01or P<0.05).3) Compared with FEN group:the levels of FINS,TGF-β1as well as HOMA-IR were lower in PIO group(P<0.01or P<0.05); the levels of FINS,TGF-β1,PICP,PIIINP and MMP-9as well as HOMA-IR,LVM and LVMI were reduced in FEN+PIO group(P<0.05).4) Compared with PIO group:HDL-C was higher but LVM and LVMI were lower in FEN+PIO group (P<0.05).(2) Animal experiment1) Compared with NC group:these indexs in MC group were decreased including SBP, FBS, FINS, HOMA-IR, TG, TC, LDL-C, HDL-C, FFA, ALT, AST, UA, BUN, and CR (P<0.01or P<0.05) but otherwise for weight (P<0.01); The mRNA and protein expressions of PPAR-α/γin ventricular in MC group were down-regulated (P<0.01). However, the protein levels of TGF-β1, Smad3, COL-Ⅰ and COL-Ⅲ, as well as cardiac hypertrophy were increased (P<0.01).2) Compared with MC group:the levels of TG, LDL-C, FFA, UA,CR in FEN group were reduced (P<0.01or P<0.05), but HDL-C and AST were elevated (P<0.01); ventricular PPAR-α mRNA were up-regulated (P<0.01); no significant difference was observed about PPAR-γ mRNA (P>0.05); the protein expressions of TGF-β1,Smad3,COL-Ⅰ and COL-Ⅲ in FEN group were decreased (P<0.01); cardiac hypertrophy index was witnessed a signicant decrease in FEN group (P<0.01). the levels of SBP, FBS, FINS, HOMA-IR, TG, TC, LDL-C and FFA were decreased in PIO group and FEN+PIO group (P<0.01or P<0.05) but HDL-C and AST were increased (P<0.01); ventricular PPAR-α/γ mRNA and protein were up-regulated (P<0.05). On contrary, the expressions of TGF-β1,Smad3,COL-Ⅰ and COL-Ⅲ in PIO group and FEN+PIO group were depressed (P<0.01or P<0.05), and a decrease was al observed in cardiac hypertrophy index (P<0.01); In FEN+PIO group UA and CR in FEN+PIO group were decreased (P<0.01or P<0.05).3) Compared with FEN group:in PIO group, the levels of SBP, FBS, FINS, HOMA-IR, TC and HDL-C were decreased (P<0.01or P<0.05), but TG (P<0.05) and UA were increased(P<0.05); the ventricular PPAR-α expression was reduced (P<0.01) but PPAR-γ mRNA was enhanced(P<0.01); the ventricular PPAR-a protein was decreased (P<0.01), but PPAR-γ protein was enhanced;the levels of TGF-β1, Smad3, COL-Ⅰ and COL-Ⅲ were decreased (P<0.01). in FEN+PIO group, the levels of SBP, FBS, FINS, HOMA-IRTC and LDL-C were decreased (P<0.05) but otherwise for HDL-C (P>0.05). However, no significant changes of PPAR-a mRNA were detected in FEN group (P>0.05).PPAR-y mRNA in FEN group was enhanced(P<0.01);the expression of TGF-β1, Smad3, COL-I and COL-III were decreased (P<0.01or P<0.05).4) Compared with PIO group:in FEN+PIO group, TG (P<0.05) and UA (P<0.01) were lower but HDL-C was increased (P<0.01). The mRNA and protein expressions of ventricular PPAR-a/y obviously were increased but COL-I level was decreased (P<0.05).Conclusions1.The clinical study has confirmed that glucose and lipid metabolism disorders exist in MS patients that have higher TGF-β1, COL-I, COL-III, MMP-9and other reconstruction-related factors as well as cardiac hypertrophic index increased, which suggests that MS patients could have ventricular remodeling.2. The clinical study has further confirmed that PPAR-α/γ agonist alone or in combination in MS patients can improve their glucose and lipid metabolism disorders, decrease reconstruction-related factors expression. It indicates that PPAR-α/γ agonists have the potential to inhibit the ventricular remodeling in MS patients, and the effects of combined therapy is more significant than single therapy3. The animal experiment has confirmed that high-fructose diet can increase blood pressure, blood sugar, lipids and induce IR in SD rats, which means MS rat models are successfully set up in our study. The increase of myocardial reconstruction-related factors and the changes in myocardial morphology suggest that the phenomenon of pathological ventricular remodeling is present in MS rat models.4. The animal experiment has further confirmed that using PPAR-α/γ agonist alone or in combination can improve glucose, lipid metabolism disorders and IR in MS rats by means of different pathways, which can decrease the expressions of various myocardial reconstruction-related factors and improve pathological ventricular remodeling.the effects of combined therapy is more significant than single therapy.5. PPAR-α/γ agonists decrease the expressions of reconstruction related factors by inhibiting the channel signal transduction of TGF-β1/Smads, thereby inhibiting pathological ventricular remodeling in MS rats.6. FEN and PIO intervention can lead to liver damage but have protective effects on kidney function. |
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