Ichinose Fumito, Buys Emmanuel S, Neilan Tomas G, Furutani Elissa M, Morgan John G, Jassal Davinder S, Graveline Amanda R, Searles Robert J, Lim Chee C, Kaneki Masao, Picard Michael H, Scherrer-Crosbie Marielle, Janssens Stefan, Liao Ronglih, Bloch Kenneth D
Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA.
Circ Res. 2007 Jan 5;100(1):130-9. doi: 10.1161/01.RES.0000253888.09574.7a. Epub 2006 Nov 30.
Myocardial dysfunction contributes to the high mortality of patients with endotoxemia. Although nitric oxide (NO) has been implicated in the pathogenesis of septic cardiovascular dysfunction, the role of myocardial NO synthase 3 (NOS3) remains incompletely defined. Here we show that mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG) are protected from myocardial dysfunction and death associated with endotoxemia. Endotoxin induced more marked impairment of Ca(2+) transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+) in the latter during endotoxemia. Endotoxin increased reactive oxygen species production in wild-type but not NOS3TG hearts, in part, because of increased xanthine oxidase activity. Inhibition of NOS by N(G)-nitro-l-arginine-methyl ester restored the ability of endotoxin to increase reactive oxygen species production and xanthine oxidase activity in NOS3TG hearts to the levels measured in endotoxin-challenged wild-type hearts. Allopurinol, a xanthine oxidase inhibitor, attenuated endotoxin-induced reactive oxygen species accumulation and myocardial dysfunction in wild-type mice. The protective effects of cardiomyocyte NOS3 on myocardial function and survival were further confirmed in a murine model of polymicrobial sepsis. These results suggest that increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+), thereby reducing myocardial dysfunction and mortality in murine models of septic shock.
心肌功能障碍导致内毒素血症患者的高死亡率。尽管一氧化氮（NO）与脓毒症性心血管功能障碍的发病机制有关，但心肌型一氧化氮合酶3（NOS3）的作用仍未完全明确。在此，我们表明心肌细胞特异性NOS3过表达的小鼠（NOS3TG）可免受与内毒素血症相关的心肌功能障碍和死亡的影响。内毒素诱导野生型心肌细胞的Ca(2+)瞬变和细胞收缩功能比NOS3TG心肌细胞有更明显的损伤，部分原因是在内毒素血症期间，后者的肌浆网Ca(2+)总负荷和肌丝对Ca(2+)的敏感性更高。内毒素增加了野生型心脏而非NOS3TG心脏中的活性氧生成，部分原因是黄嘌呤氧化酶活性增加。用N(G)-硝基-L-精氨酸甲酯抑制NOS可将内毒素增加NOS3TG心脏中活性氧生成和黄嘌呤氧化酶活性的能力恢复到内毒素刺激的野生型心脏中测得的水平。黄嘌呤氧化酶抑制剂别嘌呤醇可减轻野生型小鼠内毒素诱导的活性氧积累和心肌功能障碍。在多微生物脓毒症小鼠模型中进一步证实了心肌细胞NOS3对心肌功能和存活的保护作用。这些结果表明，心肌NO水平升高可减轻内毒素诱导的活性氧生成，并增加肌浆网Ca(2+)总负荷和肌丝对Ca(2+)的敏感性，从而降低脓毒症休克小鼠模型中的心肌功能障碍和死亡率。
