Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.

Hypothesis Open Access Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Melvin R Hayden1Email author and Suresh C Tyagi2 Cardiovascular Diabetology20032:2 https://doi.org/10.1186/1475-2840-2-2 ©  Hayden and Tyagi; licensee BioMed Central Ltd. 2003 Received: 21 November 2002Accepted: 12 February 2003Published: 12 February 2003 Abstract Background Cardiovascular disease accounts for at least 85 percent of deaths for those patients with type 2 diabetes mellitus (T2DM). Additionally, 75 percent of these deaths are due to ischemic heart disease. Hypothesis Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Testing of the hypothesis The vulnerable three arms of the eNOS reaction responsible for the generation of eNO is discussed in relation to the hypothesis: (1). The L-arginine substrate. (2). The eNOS enzyme. (3). The BH4 cofactor. Implications of the hypothesis If we view T2DM as a vascular disease initially with a later manifestation of hyperglycemia, we may be able to better understand and modify the multiple toxicities associated with insulin resistance, metabolic syndrome, prediabetes, overt T2DM, and accelerated atherosclerosis (atheroscleropathy). The importance of endothelial nitric oxide synthase, endothelial nitric oxide, tetrahydrobiopterin (BH4), L-arginine, and redox stress are discussed in relation to endothelial cell dysfunction and the development and progression of atheroscleropathy and T2DM. In addition to the standard therapies to restore endothelial cell dysfunction and stabilization of vulnerable atherosclerotic plaques, this article will discuss the importance of folic acid (5MTHF) supplementation in this complex devastating disease process. Atheroscleropathy and hyperglycemia could be early and late manifestations, respectively, in the natural progressive history of T2DM. Keywords ADMAAtherosclerosisFolic AcidOxidative stressReactive Oxygen Species (ROS)endothelial Nitric Oxide (eNO)endothelial Nitric Oxide Synthase (eNOS) (NOS-3) Background The historical discovery of the enzyme family nitric oxide synthases (NOS) in 1989 is relatively recent and we now know there are three distinct isoforms of NOS: neural NOS-1 (nNOS); inducible NOS-2 (iNOS); and endothelial NOS-3 (eNOS). These three isoforms were discovered in the above order from 1991–1994 [1]. eNOS, the rate limiting enzyme responsible for the production of endothelial derived nitric oxide (eNO) was sequenced and cloned in 1992 [2, 3]. Each NOS enzyme has its own unique amino acid structure sharing some 50 percent homology indicating a common ancestral background. Additionally, each NOS isoform is transcribed from a separate gene (table 1). Table 1 Comparisons of the human NOS enzymes nNOS NOS-1 Chromosome 12 Amino acids 1434 aa 161 kDa high Ca++ requirement iNOS NOS-2 Chromosome 17 Amino acids 1153 aa 131 kDa low Ca++ requirement eNOS NOS-3 Chromosome 7 Amino acids 1203 aa 133 kDa high Ca++ requirement Nitric oxide, voted the molecule of the year by Science Magazine in 1992 [4] has been shown to be an extremely important signaling molecule in the cardiovascular system and in 1998 Furchgott RF, Ignarro LJ, and Murad F. were awarded the Nobel Prize in Medicine and Physiology "for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system" (tables 2,3). Table 2 The positve protective effects of eNOS 1. Promotes vasodilatation of vascular smooth muscle. 2. Counteracts smooth muscle cell proliferation. 3. Decreases platelet adhesiveness. 4. Decreases adhesiveness of the endothelial layer to WBCs "Teflon effect". 5. Anti-inflammatory. 6. Anti-oxidant. It scavenges reactive oxygen species, locally. Acts as a chain – breaking antioxidant to scavenge ROS. 7. Anti-fibrotic. When NO is normal or elevated MMPs are low and conversely if NO is low MMPs are elevated and active. 8. NO has diverse anti-atherosclerotic actions on the arterial vessel wall: including antioxidant effects by direct scavenging of ROS – RNS acting as chain breaking antioxidants. Table 3 Janus – faced properties of NO GOOD BAD eNO, nNO iNO * Chromosomes 7,12 Chromosome 17 Duration: Seconds to minutes Duration: Hours to days Signaling molecule. Killer molecule. Regulated: small bursts Unregulated: larger bursts and longer duration Cytoprotective Cytotoxic *In host defense mechanisms iNO does just what we want it to, i.e. it kills invading organisms. Inducible NO can also be thought of as inflammatory NO. Paradoxically, in both acute and chronic inflammatory states iNO also kills the native hosts cells in the immediate surrounding area. This relatively brief and recent history of NOS and NO is in contrast to the ancient history of atherosclerosis which dates to the time of the Egyptians. The theories of atherosclerosis are legion and the atherosclerologists of today have a proud history upon which to build for the future [5]. The endothelial cell, such a central player, responsible for remodeling of the arterial vessel wall in atherosclerosis (intimopathy) and responsible for the synthesis of eNOS and subsequent eNO production will be discussed and related to the accelerated atherosclerosis (atheroscleropathy) associated with type 2 diabetes mellitus (T2DM) [5, 8–11]. This review will discuss dysfunction of the eNOS enzyme and its potential to uncouple, resulting in the endothelial cell becoming a net producer of damaging superoxide (O2') instead of the protective eNO (tables 4,5) [6]. The lack of eNO from the endothelial cell is related to the development of atheroscleropathy and is related to the underproduction and / or the excessive consumption of eNO by redox stress. The uncoupling of this complex enzyme will aid in the understanding of the development of atheroscleropathy and the role of oxidative and reductive stress (redox stress) in patients with T2DM [7, 8]. Table 4 Lab – garbage acronym Factors related to eNOS dysfunction with decreased NO. factors known to uncouple the eNOS enzyme. L – Lipids LDL – Cholesterol elevated both native and oxidized. Elevated Triglycerides of metabolic syndrome. Decreases or impairs dimethylarginine dimethylaminohydrolase (DDAH). Decline in DDAH activity. Increase in ADMA activity. A – Arginine (L-arginine) decreased or impaired: By competitive interaction with ADMA (asymmetric dimethylarginine) an endogenous nitric oxide synthase inhibitor. Elevated in proatherogenic conditions. ACE, Ang II, endothelin, hypertension, insulin resistance, prediabetes, T2DM, and hyperhomocysteinemia. B – BH4 Decreased or impaired Folic acid regeneration of the cofactor BH4 i.e. BH2 → BH4 with 5 methyl tetrahydrofolate (5-MTHF) active form of folic acid. G – Glucose (...truncated)