| 王理亚,单艳华,刘永萍,等.PPAR-α的激活对心力衰竭早期心肌功能的机制研究[J].安徽医药,2022,26(4):754-759. |
| PPAR-α的激活对心力衰竭早期心肌功能的机制研究 |
| Mechanism of activation of PPAR-α in myocardial function in the early stage of heart failure |
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| DOI：10.3969/j.issn.1009-6469.2022.04.026 |
| 中文关键词: 心力衰竭 过氧化物酶体增殖物激活受体 脂肪酸氧化 离体心脏灌流 心肌功能 |
| 英文关键词: Heart failure Peroxisome proliferator-activated receptors Fatty acid oxidation Perfusion of isolated heart Myo cardial function |
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| 中文摘要: |
| 目的研究过氧化物酶体增殖物激活受体 -α(PPAR-α)的激活在心力衰竭早期中的作用，并揭示其作用机制。方法 2018年 1月至 2020年 1月，通过横向主动脉缩窄( TAC)手术构建心力衰竭模型，将 20只 C57BL/6小鼠按随机数字表法随机分为 TAC-DTG组、 TAC-tTA组、 Sham-DTG组、 Sham-tTA组，每组 5只。 TCA术后 5周用高效液相色谱法( HPLC)检测 ATP并计算磷酸肌酸 /ATP水平； TAC术后 8周用逆转录 -聚合酶链反应( RT-PCR)法检测 PPAR-α及其靶基因的 mRNA表达；用经胸超声心动图检测左心室舒张末期内径( LVDd)、舒张期 LV后壁( LVPWd)及射血分数( EF)；检测心脏重量与体重和胫骨长度及肺部重量与胫骨长度的比值( HW/BW、HW/TL、LW/TL)；用 Masson Trichrome染色检测心肌细胞横截面积、心肌纤维化程度； RT-PCR法检测脑钠肽( BNP)、 I型胶原 α1(Colla1)、 Ⅲ型胶原 α1(Col3a1)mRNA表达；用离体心脏灌流实验检测棕榈酸氧化速率、葡萄糖氧化速率。结果 TAC术后 5周， TAC-DTG组小鼠 ATP浓度［(13.33±0.83)nmol/mg比( 9.56±1.05)nmol/mg］和磷酸肌酸 /ATP水平［( 2.21±0.13)比( 1.66±0.09)］均明显高于 TAC-tTA组； TAC术后 8周， TAC组小鼠 PPAR-α［( 0.64±0.05)比( 1.00±0.04)］、 CPT1［(0.56±0.06)比( 1.00±0.06)］FATP1［(0.40±0.05)(1.00±0.07)］、 CD36［(0.76±0.15)(1.00±0.20)］mRNA表达水平均明显高于 Sham组小鼠； TAC组小鼠LV、Dd［(4.41±0.07)mm比比( 4.02±0.10)mm］、 LVPWd［( 0.87比±0.02)mm比( 0.74±0.01)mm］、 EF［( 37.22±1.90)%比( 64.91±2.34)%］较 Sham组小鼠明显减弱； TAC-DTG组小鼠 HB/BW［( 6.26±0.18)比( 7.21±0.29)］、 HW/TL［( 8.80±0.27)比( 10.56±0.54)］、 LW/TL［( 13.67±0.76)( 16.97±1.25)］较 TAC-tTA组小鼠明显减弱； TAC-DTG组小鼠心肌细胞横截面积［( 694.64±23.31)μm3比( 766.90±20.98)μm3］、心肌纤维化程度［( 4.25±0.99)%比( 8.24±1.08)%］较 TAC-tTA组小鼠明显减小； TAC-DTG组小鼠 BNP［( 5.29±1.02)比( 9.33±1.42)］、 Col1a1［( 2.76±0.19)比( 4.40±0.33)］、 Col3a1［( 3.08±0.21)比(7.80±2.05)］ mRNA表达水平较 TAC-tTA组小鼠明显降低； TAC-DTG组小鼠棕榈酸氧化速率［( 0.52±0.06)μmol/g比( 0.28±0.03)μmol/g］较 TAC-tTA组小鼠明显加快，而葡萄糖氧化速率［(237.31±8.96)nmol/g比( 267.16±14.93)nmol/g］较 TAC-tTA组小鼠明显减慢。结论心力衰竭早期激活 PPAR-α可通过调节脂肪酸氧化( fatty acid oxidation，FAO)维持其心肌功能和能量，并减轻心肌重塑，提示在心衰早期激活 PPAR-α可作为其早期治疗的有效策略。 |
| 英文摘要: |
| Objective To study the role of activation of peroxisome proliferator-activated receptor-α (PPAR-α) in the early stage of heart failure and to reveal its mechanism of action.Methods From January 2018 to January 2020,A heart failure model was estab lished by transverse aortic coarctation (TAC) surgery, and 20 C57BL/6 mice were randomly assigned into TAC-DTG group, TAC-tTA group, Sham-DTG group, and Sham-tTA group according to the random number table method, 5 cases in each group. High performanceliquid chromatography (HPLC) was used to detect ATP and creatine phosphocreatine/ATP levels at 5 weeks after TCA. PPAR-α and its mRNA expression of target genes were detected by reverse transcription-polymerase chain reaction (RT-PCR) at 8 weeks after TAC. Left ventricular end-diastolic diameter (LVDd), LV posterior wall in diastole (LVPWd) and ejection fraction (EF) were measured bytransthoracic echocardiography. The ratio of heart weight with body weight and tibia length, and the ratio of lung weight with tibialength (HW/BW, HW/TL, LW/TL) were measured. The cross-sectional area of cardiomyocytes and the degree of myocardial fibrosiswere detected by Masson Trichrome staining. The mRNA expression of brain natriuretic peptide (BNP), type I collagen α1 (Colla1) andtype Ⅲ collagen α1 (Col3a1) were detected by RT-PCR. The rate of palmitic acid oxidation and glucose oxidation were detected by iso lated heart perfusion experiment.Results 5 weeks after TAC, the ATP concentration [(13.33±0.83) nmol/mg vs. (9.56±1.05) nmol/mg] and phosphocreatine/ATP levels [(2.21±0.13) vs. (1.66±0.09)] were significantly higher than those in the TAC-tTA group. 8 weeks after TAC, the PPAR-α [(0.64±0.05) vs. (1.00±0.04)], CPT1 [(0.56±0.06) vs. (1.00±0.06)], FATP1 [(0.40±0.05) vs. (1.00±0.07)], CD36 [(0.76±0.15) vs. (1.00±0.20)] mRNA expression levels were significantly higher than those in the Sham group. The LVDDd [(4.41±0.07) mm vs. (4.02±0.10) mm], LVPWd [(0.87±0.02) mm vs. (0.74±0.01) mm], EF [(37.22±1.90)% vs. (64.91±2.34)%] of mice in the TAC group were significantly weakened than those in the Sham group. The HB/BW [(6.26±0.18) vs. (7.21±0.29)], HW/TL [(8.80±0.27) vs. (10.56±0.54)], LW/TL [(13.67±0.76) vs. (16.97±1.25)] of mice in the TAC-DTG group were significantly attenuated compared with TACtTA group. Cross-sectional area of cardiomyocytes [(694.64±23.31) μm3 vs. (766.90±20.98) μm3], the degree of myocardial fibrosis [(4.25±0.99)% vs. (8.24±1.08)%] of mice in TAC-DTG group were significantly lower than those in the TAC-tTA group. mRNA expres sion levels of BNP [(5.29±1.02) vs. (9.33±1.42)], Col1a1 [(2.76±0.19) vs. (4.40±0.33)], Col3a1 [(3.08±0.21) vs. (7.80±2.05)] in the TACDTG group were significantly lower than those in TAC-tTA group. The acid oxidation rate [(0.52±0.06) μmol/g vs. (0.28±0.03) μmol/g] was significantly faster than that in the TAC-tTA group, while the rate of glucose oxidation [(237.31±8.96) nmol/g vs. (267.16±14.93) nmol/g] was significantly slower than that in the TAC-tTA group.Conclusion Activation of PPAR-α in the early stage of heart failurecan maintain its myocardial energy and reduce myocardial remodeling by regulating fatty acid oxidation (FAO), which indicates that ac tivating PPAR-α can be an effective strategy for the treatment of heart failure. |
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