Nitric oxide (NO) has long been known as endothelium-derived relaxing factor. It is a vasodilator, modulating vascular tone, blood pressure and hemodynamics, a role exploited by nitrate donor therapy for angina, heart failure, pulmonary hypertension and erectile dysfunction. In addition, its powerful antioxidant, anti-inflammatory and antithrombotic actions are antiatherogenic with antiatherothrombotic impact. NO signaling modulates skeletal muscle and myocardial contractility and metabolism and is intimately linked with insulin signaling. Vascular and muscle NO signaling coordinate skeletal muscle and myocardial energy demand with supply and are critical for both carbohydrate and fatty acid total-body homeostasis. NO signaling in mitochondria underlies much of NO’s metabolic effect, which, at low physiologic levels, links cellular energy demand with mitochondrial energy supply, while beneficially affecting mitochondrial oxidative stress and calcium handling. Mitochondria are also the site for the life-threatening deleterious effects arising from inflammation-related excessive NO levels. NO-deficient states are characterized by cell senescence, oxidative stress, inflammation, endothelial dysfunction, vascular disease, insulin resistance and type 2 diabetes mellitus. NO-enriching therapy would be expected to be of benefit not only for its hemodynamic but also for its metabolic impact. In contrast, strategies are needed to curtail excessive NO in states such as septic shock.

1.
Spier SA, Delp MD, Stallone JN, Dominguez JM 2nd, Muller-Delp JM: Exercise training enhances flow-induced vasodilation in skeletal muscle resistance arteries of aged rats: role of PGI2 and nitric oxide. Am J Physiol Heart Circ Physiol 2007;292:H3119–H3127.
2.
Clementi E, Nisoli E: Nitric oxide and mitochondrial biogenesis: a key to long-term regulation of cellular metabolism. Comp Biochem Physiol A Mol Integr Physiol 2005;142:102–e110.
3.
Marsh N, Marsh A: A short history of nitroglycerine and nitric oxide in pharmacology and physiology. Clin Exp Pharmacol Physiol 2000;27:313–319.
4.
The Nobel Prize in Physiology or Medicine. Nobelprize.org. 2012. http://www.nobelprize.org/nobel_prizes/medicine/.
5.
Ignarro LJ: Preface to this special journal issue on nitric oxide chemistry and biology. Arch Pharm Res 2009;32:1099–1101.
6.
Kone BC, Kuncewicz T, Zhang W, Yu ZY: Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. Am J Physiol Renal Physiol 2003;285:F178–F190.
7.
Lundberg JO: Nitric oxide metabolites and cardiovascular disease. Markers, mediators, or both? J Am Coll Cardiol 2006;47:580–581.
8.
Miller MR, Megson IL: Recent developments in nitric oxide donor drugs. Br J Pharmacol 2007;151:305–321.
9.
Munzel T, Feil R, Mulsch A, Lohmann SM, Hofmann F, Walter U: Physiology and pathophysiology of vascular signaling controlled by guanosine 3′,5′-cyclic monophosphate-dependent protein kinase. Circulation 2003;108:2172–2183.
10.
Lima B, Forrester MT, Hess DT, Stamler JS: S-Nitrosylation in cardiovascular signaling. Circ Res 2010;106:633–646.
11.
Parihar MS, Nazarewicz RR, Kincaid E, Bringold U, Ghafourifar P: Association of mitochondrial nitric oxide synthase activity with respiratory chain complex I. Biochem Biophys Res Commun 2008;1;366:23–28.
12.
Gutierrez J, Ballinger SW, Darley-Usmar VM, Landar A: Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells. Circ Res 2006;99:924–932.
13.
Nisoli E, Carruba MO: Nitric oxide and mitochondrial biogenesis. J Cell Sci 2006;119:2855–2862.
14.
Dedkova EN, Blatter LA: Modulation of mitochondrial Ca2+ by nitric oxide in cultured bovine vascular endothelial cells. Am J Physiol Cell Physiol 2005;289:C836–C845.
15.
Erusalimsky JD, Moncada S: Nitric oxide and mitochondrial signaling: from physiology to pathophysiology. Arterioscler Thromb Vasc Biol 2007;27:2524–2531.
16.
Duchen MR: Roles of mitochondria in health and disease. Diabetes 2004;53(suppl 1):S96–S102.
17.
Guarente L: Mitochondria – a nexus for aging, calorie restriction, and sirtuins? Cell 2008;132:171–176.
18.
Gutierrez J, Ballinger SW, Darley-Usmar VM, Landar A: Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells. Circ Res 2006;99:924–932.
19.
Zenebe WJ, Nazarewicz RR, Parihar MS, Ghafourifar P: Hypoxia/reoxygenation of isolated rat heart mitochondria causes cytochrome c release and oxidative stress; evidence for involvement of mitochondrial nitric oxide synthase. J Mol Cell Cardiol 2007;43:411–419.
20.
Mitsuishi M, Miyashita K, Itoh H: cGMP rescues mitochondrial dysfunction induced by glucose and insulin in myocytes. Biochem Biophys Res Commun 2008;21;367:840–845.
21.
Rakhit RD, Mojet MH, Marber MS, Duchen MR: Mitochondria as targets for nitric oxide-induced protection during simulated ischemia and reoxygenation in isolated neonatal cardiomyocytes. Circulation 2001;103:2617–2623.
22.
Crouser ED: Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 2004;4:729–741.
23.
Kingwell BA: Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. FASEB J 2000;14:1685–1696.
24.
Begum N, Sandu OA, Ito M, Lohmann SM, Smolenski A: Active Rho kinase (ROK-alpha) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. J Biol Chem 2002;277:6214–6222.
25.
Higaki Y, Hirshman MF, Fujii N, Goodyear LJ: Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle. Diabetes 2001;50:241–247.
26.
Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G: Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 2006;17:571–588.
27.
Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL: Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387–389.
28.
Hayden MR, Tyagi SC: Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Cardiovasc Diabetol 2003;2:2.
29.
Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S: Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9:1370–1376.
30.
Levonen AL, Patel RP, Brookes P, Go YM, Jo H, Parthasarathy S, Anderson PG, Darley-Usmar VM: Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases. Antioxid Redox Signal 2001;3:215–229.
31.
Förstermann U: Nitric oxide and oxidative stress in vascular disease. Pflügers Arch 2010;459:923–939.
32.
Kim F, Pham M, Maloney E, Rizzo NO, Morton GJ, Wisse BE, Kirk EA, Chait A, Schwartz MW: Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler Thromb Vasc Biol 2008;28:1982–1988.
33.
Cooke JP: Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000;20:2032–2037.
34.
Colombo MG, Andreassi MG, Paradossi U, Botto N, Manfredi S, Masetti S, Rossi G, Clerico A, Biagini A: Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298 → Asp polymorphism) to the presence, extent, and severity of coronary artery disease. Heart 2002,87:525–528.
35.
Romero MJ, Platt DH, Tawfik HE, Labazi M, El-Remessy AB, Bartoli M, Caldwell RB, Caldwell RW: Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res 2008;102:95–102.
36.
Kim F, Gallis B, Corson MA: TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Am J Physiol Cell Physiol 2001;280:C1057–C1065.
37.
Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R: Metabolic syndrome. A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005;111:1448–1454.
38.
Hsueh WA, Quinones MJ: Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003;92(suppl):10J–17J.
39.
Kingwell BA: Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. FASEB J 2000;14:1685–1696.
40.
Davies PF, Civelek M, Fang Y, Guerraty MA, Passerini AG: Endothelial heterogeneity associated with regional athero-susceptibility and adaptation to disturbed blood flow in vivo. Semin Thromb Hemost 2010;36:265–275.
41.
Suvorava T, Lauer N, Kojda G: Physical inactivity causes endothelial dysfunction in healthy young mice. J Am Coll Cardiol 2004;44:1320–1327.
42.
Libby P: Inflammation in atherosclerosis. Nature 2002;420:868–874.
43.
Widlansky ME, Gokce N, Keaney JJ, Vita JA: The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42:1149–1160.
44.
Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, Vollenweider P, Pedrazzini T, Nicod P, Thorens B, Scherrer U: Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001;104:342–345.
45.
Rizzo NO, Maloney E, Pham M, Luttrell I, Wessells H, Tateya S, Daum G, Handa P, Schwartz MW, Kim F: Reduced NO-cGMP signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arterioscler Thromb Vasc Biol 2010;30:758–765.
46.
Zhang Y, Janssens SP, Wingler K, Schmidt HH, Moens AL: Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 2011;301:H634–H646.
47.
Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO: Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005;310:314–317.
48.
Jankowski P, Safar ME, Benetos A: Pleiotropic effects of drugs inhibiting the renin-angiotensin-aldosterone system. Curr Pharm Des 2009;15:571–584.
49.
Javed U, Deedwania PC: Angiotensin receptor blockers: novel role in high-risk patients. Cardiol Clin 2008;26:507–526.
50.
Kamp O, Metra M, Bugatti S, Bettari L, Dei Cas A, Petrini N, Dei Cas L: Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release. Drugs 2010;70:41–56.
51.
Schwartz BG, Levine LA, Comstock G, Stecher VJ, Kloner RA: Cardiac uses of phosphodiesterase-5 inhibitors. J Am Coll Cardiol 2012;59:9–15.
52.
Liao JK, Laufs U: Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89–118.
53.
Heemskerk S, Masereeuw R, Russel FG, Pickkers P: Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nat Rev Nephrol 2009;5:629–640.
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