We investigated the ability of S-nitroso-N-acetylcyseine (SNAC) to prevent structural and functional myocardial alterations in hypercholesterolemic mice. C57BL6 wild-type (WT) and LDL-R-/- male mice (S) were fed a standard diet for 15 days. LDL-R-/- mice (S) showed an 11% increase in blood pressure, 62% decrease in left atrial contractility, and lower CD40L and eNOS expression relative to WT. LDL-R-/- mice fed an atherogenic diet for 15 days (Chol) showed significant increased left ventricular mass compared to S, which was characterized by: (1) 1.25-fold increase in the LV weight/body weight ratio and cardiomyocyte diameter; (2) enhanced expression of the NOS isoforms, CD40L, and collagen amount; and (3) no alteration in the atrial contractile performance. Administration of SNAC to Chol mice (Chol + SNAC) (0.51 μmol/kg/day for 15 day, IP) prevented increased left ventricular mass, collagen deposit, NOS isoforms, and CD40L overexpression, but it had no effect on the increased blood pressure or atrial basal hypocontractility. Deletion of the LDL receptor gene in mice resulted in hypertension and a marked left atrial contractile deficit, which may be related to eNOS underexpression. Our data show that SNAC treatment has an antiinflammatory action that might contribute to prevention of structural and functional myocardial alterations in atherosclerotic mice independently of changes in blood pressure. © 2008 Lippincott Williams & Wilkins, Inc.5117885Molkentin, J.D., Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs (2004) Cardiovasc Res, 63, pp. 467-475Ozaki, M., Kawashima, S., Yamashita, T., Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion (2002) Circ J, 66, pp. 851-856Funakoshi, H., Kubota, T., Kawamura, N., Disruption of inducible nitric oxide synthase improves β-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy (2002) Circ Res, 90, pp. 959-965Lee, T.M., Lin, M.S., Chou, T.F., Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits (2006) Am J Physiol Heart Circ Physiol, 288, pp. H1352-H1358Nakagami, H., Takemoto, M., Liao, J., NADPH oxidase-derived superoxide anion mediates angiotens II-induced cardiac hypertrophy (2003) J Mol Cell Cardiol, 35, pp. 851-859Lang, D., Mosfer, S.I., Shakesby, A., Coronary microvascular endothelial cell redox state in left ventricular hypertrophy: The role of angiotensin II (2000) Circ Res, 86, pp. 463-469Fredersdorf, S., Thumann, C., Ulucan, C., Myocardial hypertrophy and enhanced left ventricular contractility in Zucker diabetic fatty rats (2004) Cardiovasc Pathol, 13, pp. 11-19Dash, R., Schmidt, A.G., Pathak, A., Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy (2003) Cardiovasc Res, 57, pp. 704-714Barouch, L.A., Cappola, T.P., Harrison, R.W., Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice (2003) J Mol Cell Cardiol, 35, pp. 637-644Matsuoka, H., Nakata, M., Kohno, K., Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats (1996) Hypertension, 27, pp. 14-18Krieger, M.H., Santos, K.F.R., Shishido, S.M., Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice (2006) Nitric Oxide, 14, pp. 12-20Schoenbeck, U., Libby, P., The CD 40/CD154 receptor/ligand dyad (2001) Cell Mol Life Sci, 58, pp. 4-43Urbich, C., Dernbach, E., Aicher, A., CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species (2002) Circulation, 106, pp. 981-986André, P., Nannizzi-Alaimo, L., Prasad, S.K., Platelet derived CD40L: The switch-hitting player of cardiovascular disease (2002) Circulation, 106, pp. 896-899Vishnevetsky, D., Kiyanista, V.A., Gandhi, P.J., CD40 ligand: A novel target in the fight against cardiovascular disease (2004) Ann Pharmacother, 38, pp. 1500-1508Ueland, T., Aukrust, P., Yndestad, A., Soluble CD40 ligand in acute and chronic heart failure (2005) Eur Heart J, 26, pp. 1101-1017Ricardo, K.F., Shishido, S.M., de Oliveira, M.G., Characterization of the hypotensive effect of S-nitroso-N-acetylcysteine in normotensive and hypertensive conscious rats (2002) Nitric Oxide, 7, pp. 57-66Krege, J.H., Hodgin, J.B., Hagaman, J.R., A noninvasive computerized tail cuff system for measuring pressure in mice (1995) Hypertension, 25, pp. 1111-1115Besse, J.C., Furchgott, R.F., Dissociation constants and relative efficacies of agonists acting on alpha adrenergic receptors in rabbit aorta (1976) J Pharmacol Exp Ther, 197, pp. 66-78Salt, P.J., Inhibition of noradrenaline uptake2 in the isolated rat heart by steroids, clonidine and methoxylated phenylethylamines (1972) Eur J Pharmacol, 20, pp. 329-340Iversen, L.L., Salt, P.J., Inhibition of catecholamine uptake2 by steroids in the isolated rat heart (1970) Br J Pharmacol, 40, pp. 528-530Furchgott, R.F., Bursztyn, P., Comparison of dissociation constants and of relative efficacies of selected agonists on parasympathetic receptors (1967) Ann N Y Acad Sci, 144, pp. 882-889Haddad, G.E., Coleman, B.R., Zhao, A., Regulation of atrial contraction by PKA and PKC during development and regression of eccentric cardiac hypertrophy (2005) Am J Physiol Heart Circ Physiol, 288, pp. 695-704Junqueira, L.C., Bignolas, G., Brentani, R.R., Picrosirius red staining plus polarization microscopy, a specific method for collagen detection in tissue sections (1979) Histochem J, 11, pp. 447-455Shirani, J., Pick, R., Roberts, W.C., Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death (2000) J Am Coll Card, 35, pp. 36-44Garcia, J.A.D., Tornatore, T.F., Krieger, M.H., Digital image analysis software for morphometric quantitation in tissues and cells (2006) Dissertações e teses: Produção Científica da UNICAMP: José Antonio Dias Garcia, pp. 58-72. , http://libdigi.unicamp.br/document/list, Available atArmstrong, A.T., Binkley, P.F., Baker, P.B., Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation (1998) J Am Coll Cardiol, 32, pp. 704-710Tambascia, R.C., Fonseca, P.M., Corat, P.D.C., Expression and distribution of NOS1 and NOS3 in the myocardium of angiotensin II infused rats (2000) Hypertension, 37, pp. 1423-1428Sundström, J., Lind, L., Vessby, B., Dyslipidemia and an Unfavorable Fatty Acid Profile Predict Left Ventricular Hypertrophy 20 Years Later (2001) Circulation, 103, pp. 836-841Genda, S., Miura, T., Miki, T., K(ATP) channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia (2002) J Am Coll Cardiol, 40, pp. 1339-1346Li, H., Forstermann, U., Nitric oxide in the pathogenesis of vascular disease (2000) J Pathol, 190, pp. 244-254Barouch, L.A., Harrison, R.W., Skaf, M.W., Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms (2002) Nature, 416, pp. 337-339Nadruz Jr, W., Lagosta, V.J., Moreno, H.J., Simvastatin prevents load-induced protein tyrosine nitration in overloaded-induced hearts (2004) Hypertension, 43, pp. 1060-1066Takimoto, E., Champion, H.C., Li, M., Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load (2005) J Clin Invest, 115, pp. 1221-1231Henn, V., Slupsky, J.R., Grafe, M., CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells (1998) Nature, 391, pp. 591-594Oliveira, H.C.F., Cosso, R.G., Alberici, L.C., Oxidative stress in atherosclerosis-prone mouse is due to low antioxidant capacity of mitochondria (2004) Faseb J, 19, pp. 278-280Bernal-Mizrachi, C., Gates, A.C., Weng, S., Vascular respiratory uncoupling increases blood pressure and atherosclerosis (2005) Nature, 26, pp. 502-506Stys, T., Stys, A., Paczwa, P., Decreased hypotensive responsiveness to nitric oxide donor S-nitroso N-acetyl-DL-penicillamine (SNAP) in spontaneously hypertensive (SHR) rats (1998) J Physiol Pharmacol, 49, pp. 37-49Calderone, A., Thaik, C.M., Takahashi, N., Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth promoting effects of norepinephrine in cardiac myocytes and fibroblasts (1998) J Clin Invest, 101, pp. 812-818Kempf, T., Wollert, K.C., Nitric oxide and the enigma of cardiac hypertrophy (2004) Bioessays, 6, pp. 608-615