Abstract
Theoretical inferences, based on biophysical, biochemical, and biosemiotic considerations, are related here to the pathogenesis of cardiovascular disease, diabetes, and other degenerative conditions. We suggest that the “daytime” job of endothelial nitric oxide synthase (eNOS), when sunlight is available, is to catalyze sulfate production. There is a striking alignment between cell types that produce either cholesterol sulfate or sulfated polysaccharides and those that contain eNOS. The signaling gas, nitric oxide, a well-known product of eNOS, produces pathological effects not shared by hydrogen sulfide, a sulfur-based signaling gas. We propose that sulfate plays an essential role in HDL-A1 cholesterol trafficking and in sulfation of heparan sulfate proteoglycans (HSPGs), both critical to lysosomal recycling (or disposal) of cellular debris. HSPGs are also crucial in glucose metabolism, protecting against diabetes, and in maintaining blood colloidal suspension and capillary flow, through systems dependent on water-structuring properties of sulfate, an anionic kosmotrope. When sunlight exposure is insufficient, lipids accumulate in the atheroma in order to supply cholesterol and sulfate to the heart, using a process that depends upon inflammation. The inevitable conclusion is that dietary sulfur and adequate sunlight can help prevent heart disease, diabetes, and other disease conditions.
Highlights
The nitric oxide synthases (NOSs) are a family of three distinct highly regulated isoforms of an enzyme class that produces nitric oxide (NO) [1,2]
The class consists of two constitutive forms, endothelial NOS and neuronal NOS, which are activated by calcium-bound calmodulin, and an inducible form, iNOS, which is insensitive to calcium. eNOS, even when activated, produces only a small fraction of the amount of NO typically produced by iNOS. eNOS and nNOS are capable of producing superoxide (O2−) in the absence of their substrate L-arginine, and this is generally viewed as a pathological response, we will argue otherwise in this paper
We propose that the sulfate is first produced from thiosulfate or another form of sulfane sulfur by eNOS, with superoxide as a reactive intermediate, and reacts with adenosine triphosphate (ATP) provided through glycolysis to form PAPS, which is subsequently used to produce cholesterol sulfate (Ch-S) from cholesterol
Summary
The nitric oxide synthases (NOSs) are a family of three distinct highly regulated isoforms of an enzyme class that produces nitric oxide (NO) [1,2]. ENOS is an extremely well-studied protein, much remains mysterious about its function It is expressed in the endothelial cells lining blood vessel walls, and in fibroblasts [3], cardiomyocytes [4], platelets [5], and red blood cells (RBCs) [6], among others. It maintains a “resting” state bound to the protein caveolin in the small invaginations in the membrane surface known as caveolae associated with lipid rafts on the plasma membrane [4,7]. It has been established that insulin resistance and impaired autophagy can result from inadequate supply of cholesterol and sulfate to the plasma membrane and to lysosomes
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