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. 2017 Dec 1;160(2):341-350.
doi: 10.1093/toxsci/kfx193.

L-Carnitine Attenuates Cardiac Dysfunction by Ischemic Insults Through Akt Signaling Pathway

Mei Xue  1   2 , Xu Chen  2 , Zhija Guo  2 , Xiaoqian Liu  2 , Yanping Bi  2 , Jie Yin  1 , Haiyan Hu  3 , Ping Zhu  3 , Jian Zhuang  3 , Courtney Cates  2 , Thomas Rousselle  2 , Ji Li  2
Affiliations

L-Carnitine Attenuates Cardiac Dysfunction by Ischemic Insults Through Akt Signaling Pathway

Mei Xue et al. Toxicol Sci. .

Erratum in

Abstract

We aim to investigate the cardioprotective effects of L-carnitine (LC) on cardiac function during ischemia and reperfusion (I/R) and contractile function of single cardiomyocyte. C57BL/6 J mice were randomly assigned to 5 groups: sham group; vehicle group, LC preconditioning group, LC preconditioning + LY294002 (a PI3K/Akt signaling pathway inhibitor) group (LC + LY), and LY294002 group (LY). The sham group was exposed to the open heart operation but not I/R, the other groups received 45 min ischemia/48 h reperfusion. At the end of reperfusion, echocardiography was performed on every mouse. In order to determine whether LC's cardioprotection could act directly at the level of cardiomyocytes, we also tested its effects on isolated cardiomyocytes under hypoxia condition. The expressions of p-PI3K, PI3K, Akt, p-Akt, Bax and Bcl-2 proteins were detected by immunoblotting. The results showed that LC preconditioning remarkably improved cardiac function after I/R, but the cardioprotective effect of LC was significantly weakened after the application of LY294002. We also found that LC could directly improve the contractile function of cardiomyocytes under hypoxia condition. The immunoblotting results showed that LC administration restrained myocardial apoptosis as evidenced by decreasing the level of Bax expression, increasing the levels of phosphorylation of Akt, PI3K, and Bcl-2 protein expression, but these were blocked by LYC94002. Thus, the cardioprotective effects of LC against myocardial ischemic damage and its effect on single cardiomyocyte under hypoxia may be associated with the PI3K/Akt signaling pathway.

Keywords: Akt; L-carnitine; myocardial ischemia reperfusion.

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Figures

Figure 1
Figure 1
Pre-administration of LC during the I/R improved cardiac function after 48 h of reperfusion. A, The representative Echo of the sham, vehicle, LC, LC + LY, and the LY group. B and C, I/R decreased the left ventricular EF and FS in vehicle group, LC administration improved the EF and FS, but it was blocked in the LC + LY and LY group. Values are means ± SE, n = 4–5, *p < .01 versus Sham; †p < .05 versus Vehicle; #p < .01 versus LC I/R.
Figure 2
Figure 2
A, Presence of apoptosis was confirmed by TUNEL staining and Nuclei staining (magnification 200×). B, Quantification of apoptosis was expressed by the percentage of TUNEL positive cells. *p < .05 versus Sham; †p < .05 versus Vehicle; #p < .01 versus LC I/R.
Figure 3
Figure 3
Contractile properties of cardiomyocytes isolated from C57BL/6 mice with vehicle or LC treatment after being exposed to hypoxia. Recordings are shown from vehicle and 5 mM LC treatment for both normoxic and hypoxic treated cells. A, Representative sarcomeric length change recordings are shown during contractions stimulated at a frequency of 0.5 Hz. B, Resting sarcomere length; C, Peak sarcomeric length change during contraction; D, The maximal velocity of shortening (+dL/dt); E, The maximum velocity of relaxation (−dL/dt); F, PS (normalized to the resting sarcomere length); G, time-to-90% relengthening (TR90). Values are means ± SE, n = 75–127 cells per group derived from 3 to 4 mice each. *p < .05 versus normoxia vehicle; †p < .05 versus hypoxia vehicle.
Figure 4
Figure 4
LC protects against hypoxia induced loss of intracellular Ca2+ release in cardiomyocytes. A, 340/380 ratio fluorescent imaging records of cardiomyocytes loaded with Fura2-AM Ca2+ indicator. Representative recordings of contraction induced intracellular Ca2+ changes are shown during contractions stimulated at a frequency of 0.5 Hz. B, Resting intracellular Ca2+; C, Peak Ca2+ changes during contraction. D, Maximum rate of Ca2+ change during contraction (+dF/dt); E, Maximum rate of Ca2+ change during relaxation (−dF/dt); Recordings are shown from vehicle and 5 mM LC treatment for both normoxic and hypoxic treated cells. Values are means ± SE, n = 75–127 cells per group derived from 3 to 4 mice each, *p < .05 versus normoxia vehicle; †p < .05 versus hypoxia vehicle.
Figure 5
Figure 5
LC attenuates myocardial I/R injury by regulating the PI3K/Akt pathway. A, Representative western blot of different groups. B, The relative levels of p-PI3K with different conditions. C, The relative levels of p-Akt. D, The relative ratio of Bcl-2/Bax. Data are shown as the mean ± SE from independent experiments, n = 4–5, *p < .05 versus Sham; †p < .05 versus Vehicle I/R; #p < .05 versus LC I/R.
Figure 6
Figure 6
LC (5 mM) inhibits apoptotic signaling system hypoxia treatment. A, Representative immunoblots of different groups are shown from cells in normoxic and hypoxic conditions, and in the absence or presence of LC; B, The relative levels of p-Akt; C, The relative ratio of Bcl-2/Bax. Data are shown as the mean ± SE from independent experiments, n = 3–4 mice each group, *p < .05 versus normoxia vehicle; †p < .05 versus hypoxia vehicle.
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