Endothelial Nitric Oxide Synthase (eNOS) and the Cardiovascular System: in Physiology and in Disease States

Abstract

Endothelial nitric oxide synthase (eNOS) plays a critical role in regulating and maintaining a healthy cardiovascular system. The importance of eNOS can be emphasized from the genetic polymorphisms of the eNOS gene, uncoupling of eNOS dimerization, and its numerous signaling regulations. The activity of eNOS on the cardiac myocytes, vasculature, and the central nervous system are discussed. The effects of eNOS on the sympathetic autonomic nervous system (SANS) and the parasympathetic autonomic nervous system (PANS), both of which profoundly influence the cardiovascular system, will be elaborated. The relationship between the eNOS protein with cardiovascular autonomic reflexes such as the baroreflex and the Exercise Pressor Reflex will be discussed. For example, the effects of endogenous nitric oxide (NO) are shown to be mediated by the eNOS protein and that eNOS-derived endothelial NO is most effective in regulating blood pressure oscillations via modulating the baroreflex mechanisms. The protective action of eNOS on the CVS is emphasized here because dysfunction of the eNOS enzyme is intricately correlated with the pathogenesis of several cardiovascular diseases such as hypertension, arteriosclerosis, myocardial infarction, and stroke. Overall, our current understanding of the eNOS protein with a focus on its role in the modulation, regulation, and control of the cardiovascular system in a normal physiological state and in cardiovascular diseases are discussed.

Keywords: Angiotensin; Arteriosclerosis; Baroreflex; Blood Pressure; Cardiovascular Reflex; Cyclic GMP; ENOS Dimerization; ENOS gene; ENOS polymorphism; Endothelium; Exercise Pressor Reflex; Glutamate; Hypertension; Myocardial Infarction; Nitric Oxide; Nociception; Stroke; Sympa-thetic Nervous System; Vasodilatation; Ventrolateral Medulla.

Figure 1:

Scheme of the gene encoding endothelial nitric oxide synthase (eNOS). The human eNOS gene is located at 7q35-36 and it contains 26 exons with the start transcription site designated by AUG in the promoter region; polymorphisms are indicated in the promotor region and exon 7. Scheme of the eNOS protein is also shown on the extreme right.

Figure 2:

Schematic diagram of coupled versus uncoupled endothelial nitric oxide synthase or eNOS showing that uncoupled eNOS can generate a highly toxic super radical as shown by the abbreviation O2-, the ion superoxide. Other abbreviations: O2 - Oxygen; NADPH - Nicotinamide adenine dinucleotide phosphate hydroxide; NADP+ - Nicotinamide adenine dinucleotide phosphate; FAD - Flavin adenine dinucleotide; FMN - Flavin mononucleotide; CaM - Calmodulin.

Figure 3:

A schematic diagram of how eNOS via NO causes smooth muscle relaxation in vascular smooth muscle cells. Abbreviations: cGMP – cyclic guanosine monophosphate, GTP – guanosine triphosphate, sGC – soluble guanylate cyclase, PKG – cGMP dependent protein kinase.

Figure 4:

A summary of the Exercise Pressor Reflex arc reflecting major neurotransmitters and regions of the brain that are involved. Abbreviations: NO - nitric oxide; eNOS – endothelial nitric oxide synthase; iNOS – inducible nitric oxide synthase; nNOS – neuronal nitric oxide synthase; RVLM – rostral ventrolateral medulla; CVLM – caudal ventrolateral medulla; IML – intermediolateral column of the spinal cord.