H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase.
H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase.
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DOI：
10.1161/circulationaha.112.000855
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发表时间：
2013-03-12
期刊：
影响因子：
37.8
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Kondo K;Bhushan S;King AL;Prabhu SD;Hamid T;Koenig S;Murohara T;Predmore BL;Gojon G Sr;Gojon G Jr;Wang R;Karusula N;Nicholson CK;Calvert JW;Lefer DJ
胱硫醚γ-裂解酶（CSE）通过L-半胱氨酸的酶促转化产生H2S，并在心血管稳态中起关键作用。我们研究了CSE的遗传调节和外源性H2S治疗在压力超负荷诱导的心力衰竭中的作用。在野生型（WT）、CSE敲除（KO）和心脏特异性CSE转基因（CS-CSE Tg）小鼠中进行横向主动脉缩窄（TAC）。此外，C57 BL/6 J或CSE KO小鼠接受新型-H2S供体（SG-1002）。使用超声心动图跟踪小鼠12周。我们观察到TAC后心肌和循环H2S水平降低>60%。TAC后，CSE KO小鼠表现出的心脏扩张和功能障碍明显大于WT小鼠，而CS-CSE Tg小鼠在TAC后保持了心脏结构和功能。SG-1002的H2S治疗通过上调VEGF-Akt-eNOS-一氧化氮-cGMP途径在TAC期间产生心脏保护作用，同时保留线粒体功能、减弱氧化应激和增加心肌血管密度。我们的研究结果表明，H2S水平在心力衰竭的小鼠中降低。此外，CSE在心力衰竭的心脏功能保护中起着关键作用，口服H2S治疗部分通过上调内皮型一氧化氮合酶（eNOS）和增加NO生物利用度来防止从代偿性心力衰竭向失代偿性心力衰竭的转变。
Cystathionine gamma-lyase (CSE) produces H2S via enzymatic conversion of L-cysteine and plays a critical role in cardiovascular homeostasis. We investigated the effects of genetic modulation of CSE and exogenous H2S therapy in the setting of pressure overload-induced heart failure. Transverse aortic constriction (TAC) was performed in wild-type (WT), CSE knockout (KO), and cardiac specific CSE transgenic (CS-CSE Tg) mice. In addition, C57BL/6J or CSE KO mice received a novel–H2S donor (SG-1002). Mice were followed for 12 weeks using echocardiography. We observed a >60% reduction in myocardial and circulating H2S levels following TAC. CSE KO mice exhibited cardiac dilatation and dysfunction significantly greater than WT mice following TAC and CS-CSE Tg mice maintained cardiac structure and function following TAC. H2S therapy with SG-1002 resulted in cardioprotection during TAC via upregulation of the VEGF-Akt-eNOS-nitric oxide-cGMP pathway with preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density. Our results demonstrate that H2S levels are decreased in mice in the setting of heart failure. Moreover, CSE plays a critical role in the preservation of cardiac function in heart failure and oral H2S therapy prevents the transition from compensated to decompensated heart failure in part via upregulation of endothelial nitric oxide synthase (eNOS) and increased NO bioavailability.