PPIs, cardiovascular disease risk, nitric oxide, PON1 (brief notes)

Stomach acid suppression can result in deficiencies of B12, calcium and other important nutrients. B12 is needed for tetrahydrobiopterin production which is in turn a cofactor for nitric oxide [NO] synthesis by nitric oxide synthase [NOS]. Also, nitrite is converted in the presence of stomach acid to nitrous acid, which then forms NO. So it seems plausible that the association of cardiovascular disease with long-term proton pump inhibitor [PPI] use could be due to lowered production of NO as the result of acid reduction. However, other mechanisms may be at work, and may be more significant - 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864131/ 

"The evidence obtained in the aforementioned studies suggest that the underlying mechanism for cardiovascular effects of PPIs are not directly related to acid suppression, since H2-receptor antagonists are not associated with the cardiovascular risk [45, 46]. "

Another explanation for the association is that PPIs inhibit PON1 (in vitro and in silico study):
https://pubmed.ncbi.nlm.nih.gov/31353473/ 

"Finally, apart from these, it has been identified several side effects of PPIs, such as dementia,[75] coeliac diseases,[76] microscopic colitis,[77] chronic kidney disease,[78] myocardial infarction[79] and stroke.[80]  

...

After, the pantoprazole, omeprazole and esomeprazole as PPIs were tested on paraoxonase activity of the PON1 enzyme. The inhibition effect order of drugs is pantoprazole > omeprazole > esomeprazole."

Inhibition of PON1 results in lower NO production. PPIs also directly inhibit NOS expression as well as NOS activity via inhibition of DDAH (see first linked reference above for explanation). Of course, gastric acid suppression could contribute to the overall reduction in NO from PPIs; it is hard to know what is the most important mechanism is, though the lack of association for H2 blockers seems to indicate the cause is not acid suppression by itself.

~

Really interesting review article on PON1 and nitric oxide:

Mutual Influences between Nitric Oxide and Paraoxonase 1

"In rheumatoid arthritis, an inflammatory disease in which there is an abnormal autoimmune response to oxidation of the basic amino acids in proteins, a high amount of antibodies against HDL has been found, and they are credited to PON1. The consequent inactivation of PON1 is accompanied, as in HPS, by an increase in NOx levels, especially in the genotype 192QQ [].

Maes et al. published a study that while undoubtedly narrow with reference to its demographic scope, is of high value for the deep analysis of nitrative stress and antioxidant defenses in patients suffering from mental generalized anxiety disease (GAD). This study took into account personal factors such as sex, age, body mass index, smoking habit, education, marital status, etc., along with central nervous comorbidities and their pharmacological treatments. Among the antioxidant physiological equipment, PON1 is one of the most important factors because its decrease is strongly associated to the presence of GAD. The authors reported the statistical significance of the incidence of 16 biochemical parameters including NOx, lipid peroxidation products, catalase, and protein carbonylation []."

This makes me wonder if auto-antibodies to PON1 play a role in other diseases, and also want to read up on Walford's auto-immune / immunologic  theory of aging (1964).




 

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