G, Jin Q, Giannobile WV, Ma PX. Nano-fibrous scaffold for controlled delivery of recombinant human PDGF-BB. J Control Release. 2006;112:103-110.
12.Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells. 2007;25:2896-2902.
13.Cervelli V, Gentile P, De Angelis B, et al. Application of enhanced stromal vascular fraction and fat grafting mixed with PRP in post-traumatic lower extremity ulcers. Stem Cell Res. 2011;6:103-111.
ABOUT THE AUTHOR
Dr. Robert Bowen is an Internal Medicine and Pulmonary specialist, Board Certified in Cosmetic Laser Surgery by the American Board of Laser Surgery. He is a Fellow of the American Society of Laser Medicine and Surgery and has published research articles on laser medicine. Dr. Bowen is a Diplomate of the American Board of Anti-Aging Medicine and a graduate of the Aesthetic Medicine Fellowship.
Chapter 4
Nitric Oxide: The Overlooked Molecule in Patient Care
Nathan S. Bryan, Ph.D.
Texas Therapeutics Institute, The University of Texas
Health Science Center at Houston
ABSTRACT
Although often overlooked, nitric oxide (NO) is one of the most important signaling molecules in the body. It is involved in virtually every organ system, and is responsible for modulating an astonishing variety of effects. Thus, it is no surprise to learn that a host of diseases or conditions may be caused or affected by the body’s dysregulation of NO production/signaling. Maintaining NO homeostasis is critical for optimal health and disease prevention, and developing diagnostics and therapeutics to accomplish this will have a profound effect on public health. The aim of this paper is to introduce the reader to the importance of NO, and the age-dependent decline in NO production and its consequences, NO diagnostics and therapeutic strategies for maintaining NO homeostasis will also be considered.
INTRODUCTION
Chronic diseases including heart disease, diabetes, Alzheimer’s, and cancer account for 61% of deaths worldwide. Almost 45 % of these deaths occur prematurely before the age of 70. Fortunately though, most of these deaths are preventable by diet and lifestyle modification. The common factor causal for these chronic diseases may be insufficient nitric oxide (NO). Science has now shown that certain diets and moderate exercise can restore NO and positively affect these chronic diseases. The discovery in the 1980’s of the mammalian biosynthesis of NO and its roles in the immune1,2 cardiovascular3,5 and nervous6 systems established a startling new paradigm in the history of cellular signaling mechanisms. In fact, the discovery of NO was so profound that a Nobel Prize was awarded in 1998 to the 3 US scientists responsible for its discovery.
NO is one of the most important signaling molecules in the body, and is involved in virtually every organ system where it is responsible for modulating an astonishing variety of effects. NO has been shown to be involved in and affect every biological system in humans. One can then imagine the host of diseases or conditions that may be caused or affected by the body’s dysregulation of NO production/signaling. Maintaining NO homeostasis is critical for optimal health and disease prevention, and developing diagnostics and therapeutics to accomplish this will have a profound effect on public health. NO has a number of clinical applications including: inhaled NO for premature babies with pulmonary hypertension, treatment for erectile dysfunction and systemic hypertension, and many others. In fact, the release of NO from nitroglycerin is the mechanism of action for this drug, which has been used for over 160 years for the treatment of acute angina in cardiac patients.
The first pathway to be discovered for the endogenous production of NO was that involving L-arginine. For years, scientists and physicians have investigated L-arginine supplementation as a means to enhance NO production. This strategy has been shown to work effectively in young healthy individuals with functional endothelium or in older patients with high levels of asymmetric dimethyl L-arginine (ADMA), where the supplemental L-arginine can outcompete this natural inhibitor of NO production. However, patients with endothelial dysfunction, by definition, are unable to convert L-arginine to NO and, therefore, this strategy has failed in clinical trials. In fact, the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial, concluded that L-arginine therapy (when added to standard postinfarction therapies) did not improve vascular stiffness measurements or ejection fraction, and was associated with higher postinfarction mortality.7 Thus, L-arginine should not be recommended following acute myocardial infarction (MI). However, there are also a number of studies showing benefit to patients taking L-arginine and just as many showing no benefit, no harm. Collectively, the literature suggests that strategies to enhance NO production through L-arginine supplementation are equivocal at best. Therefore there must be an alternative pathway for repleting NO in patients.
AGE-DEPENDENT DECLINE IN NITRIC OXIDE PRODUCTION
When we are young and healthy, the endothelial production of NO through L-arginine is efficient and sufficient to produce NO; however, as we age we lose our ability to synthesize endothelial derived NO. Most of the works on the activity of NO in cells and tissues agree that the bioavailability or the generation of nitric oxide synthase (NOS) derived NO decreases with aging. It has been proposed that superoxide can scavenge NO to form peroxynitrite and thereby reduce its effective concentrations in cells.8 It has also been reported that there is decreased NOS expression with aging both in constitutive and inducible isoforms.9,10 Berkowitz et al11 observed the upregulation of arginase (an enzyme that degrades the natural substrate for NOS, L-arginine) in aged blood vessels and the corresponding modulation of NOS activity. Taddei et al12 have shown that there is a gradual decline in endothelial function due to aging, with greater than 50% loss in endothelial function in the oldest age group tested as measured by forearm blood flow assays. Egashira et al13 reported more dramatic findings in the coronary circulation of aging adults whereby there was a loss of 75% of endothelium-derived nitric oxide in 70-80 year-old patients compared to young, healthy 20-year-olds. Vita et al14 demonstrated that increasing age was one predictor of abnormal endothelium-dependent vasodilation in atherosclerotic human epicardial coronary arteries. Whilst Gerhard et al15 concluded from their 1996 study that age was the most significant predictor of endothelium-dependent vasodilator responses by multiple stepwise regression analysis. Collectively, these important findings illustrate that endothelium-dependent vasodilation in resistance vessels declines progressively with increasing age. This abnormality is present in healthy adults who have no other cardiovascular risk factors, such as diabetes, hypertension, or hypercholesterolemia. Most of these studies found that impairment of endothelium-dependent vasodilation was clearly evident by the fourth decade. In contrast, endothelium-independent vasodilation does not change significantly with aging, demonstrating that the responsiveness to NO does not change; only the ability to generate it does.
These observations enable us to conclude that reduced availability of endothelium-derived NO occurs as we age and to speculate that this abnormality may create an environment that is conducive to atherogenesis and other vascular disorders. It appears that aging interrupts NO signaling at every conceivable level, from production to inactivation. Given that NO is a necessary molecule for maintenance of health and prevention of disease, restoration of NO homeostasis may provide a new treatment modality for age and age related disease.
The
