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(Circulation Research. 2007;100:130.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Prevents Myocardial Dysfunction in Murine Models of Septic Shock

Fumito Ichinose, Emmanuel S. Buys, Tomas G. Neilan, Elissa M. Furutani, John G. Morgan, Davinder S. Jassal, Amanda R. Graveline, Robert J. Searles, Chee C. Lim, Masao Kaneki, Michael H. Picard, Marielle Scherrer-Crosbie, Stefan Janssens, Ronglih Liao, Kenneth D. Bloch

From the Department of Anesthesia and Critical Care (F.I., R.J.S., M.K., K.D.B.), Massachusetts General Hospital, Boston; Cardiovascular Research Center (F.I., E.S.B., E.M.F., A.R.G., M.S.-C., K.D.B.) and Cardiac Ultrasound Laboratory (T.G.N., J.G.M., D.S.J., M.H.P., M.S.-C.), Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston Cardiac Muscle Research Laboratory (R.L.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Boston University School of Medicine (C.C.L.), Mass; Department of Cardiology and Center for Transgene Technology and Gene Therapy (S.J.), University of Leuven, Belgium.

Correspondence to Fumito Ichinose, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail fichinose{at}partners.org

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 Ca²⁺ transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca²⁺ load and myofilament sensitivity to Ca²⁺ 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 Ca²⁺ load and myofilament sensitivity to Ca²⁺, thereby reducing myocardial dysfunction and mortality in murine models of septic shock.

Key Words: nitric oxide • endotoxin • reactive oxygen species • calcium handling • myofilament

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