The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo
The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo
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DOI：
10.1007/s00395-009-0015-5
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发表时间：
2009-09-01
影响因子：
9.5
通讯作者：
Doenst, Torsten
中科院分区：
文献类型：
--
作者：
Schwarzer, Michael;Faerber, Gloria;Doenst, Torsten
将心肌中的底物氧化从脂肪酸转变为葡萄糖（底物转换）可能会改善心力衰竭时的收缩功能。我们测试了应用两种能够诱导底物转换的药物（依托莫克西和 NVP-LAB121）是否可以逆转慢性压力超负荷大鼠心力衰竭的发作。通过大鼠主动脉束带术诱导肥大1周或15周。大鼠用 CPT-1 抑制剂依托莫昔尔 [29.5 μmol/(kg 天)] 或 NVP-LAB121 [60 μmol/(kg 天)]（一种丙酮酸脱氢酶激酶抑制剂）治疗 10 天，然后通过超声心动图评估和作为离体工作心脏进行灌注。我们还通过 RT-PCR 分析了 PDH 和 CPT1 活性以及 α 和 β-MHC 的表达。主动脉束带术使心脏与体重之比 (g/kg) 在 1 周后从 3.44 +/- A 0.26 增加到 4.14 +/- A 0.48，在 15 周后从 2.80 +/- A 0.21 增加到 6.54 +/- A 0.26。 15周后射血分数受损（57 +/- A 11 vs. 73 +/- A 8%，P < 0.05），并且大鼠表现出心力衰竭的迹象。所有组中的总 PDH 活性均相同。 CPT-1 活性在 1 周后没有变化，但在 15 周后下降（P < 0.01）。依托莫克西和NVP-LAB121都不影响体内心脏功能，但依托莫克西改善了离体心脏的功能。这些药物不会影响总 PDH 和 CPT-1 活性，但会增加 PDH 活性状态，防止心力衰竭中 PDK4 表达的减少，增加 α 和 β-MHC 表达，并将离体工作大鼠心脏中的底物氧化转向葡萄糖。总之，底物转换的药理学诱导与肌原纤维亚型表达的变化相关，但不能逆转体内心力衰竭。体外功能的改善值得进一步研究。
Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may improve contractile function in heart failure. We tested whether application of two agents (etomoxir and NVP-LAB121) capable of inducing a substrate-switch reverts the onset of heart failure in rats with chronic pressure-overload. Hypertrophy was induced by aortic banding in rats for 1 or 15 weeks. Rats were treated for 10 days with the CPT-1-inhibitor etomoxir [29.5 mu mol/(kg day)] or with NVP-LAB121 [60 mu mol/(kg day)], a pyruvate-dehydrogenase-kinase-inhibitor, before assessment by echocardiography and perfusion as isolated working hearts. We also analyzed PDH- and CPT1-activity and expression of alpha- and beta-MHC by RT-PCR. Aortic banding increased heart-to-body-weight-ratio (g/kg) from 3.44 +/- A 0.26 to 4.14 +/- A 0.48 after 1 week and from 2.80 +/- A 0.21 to 6.54 +/- A 0.26 after 15 weeks. Ejection fraction was impaired after 15 weeks (57 +/- A 11 vs. 73 +/- A 8%, P < 0.05) and rats exhibited signs of heart failure. Total PDH activity was the same in all groups. CPT-1 activity was unchanged after 1 week but decreased after 15 weeks (P < 0.01). Neither etomoxir nor NVP-LAB121 affected cardiac function in vivo, but etomoxir improved function of the isolated heart. The drugs did not affect total PDH and CPT-1 activity, but increased PDH-activity status, prevented a decrease in PDK4 expression in heart failure, increased alpha and beta-MHC expression and shifted substrate oxidation toward glucose in the isolated working rat heart. In conclusion, pharmacologic induction of substrate-switching is associated with changes in myofibrillar isoform expression but does not reverse heart failure in vivo. The improvement of function in vitro deserves further investigation.