Nature-oriented upbringing and significant moments of life that accompanied Innokenty Innokentyevich Vinokurov from childhood became the basis for the formation of his personality as a surgeon, scientist, and writer. The formation of a professional's personality took place in the extreme conditions of the Far North, then in the team of a large scientific institution, which motivated the search for health-saving methods of surgical interventions and constant self-improvement of the level of one's qualifications. An innovative approach to professional activity has become the core of many scientific discoveries and inventions. Achievement of qualitatively significant results in the field of practical surgery, organization of the health care system, scientific activities were successfully combined with the development of the creative potential of Vinokurov I. as a writer. Bright literary works created by a talented writer are evidence of the versatility of his talent. The source of his success was not only natural talent, character traits, but also love for his native land and for his people. The life of a multifaceted personality was brutally interrupted by the terrible epidemic of the 21st century caused by the new coronavirus infection COVID-19. The study of the personality of the outstanding son of the Evenk people Innokenty Vinokurov is an actual topic of scientific knowledge of various fields of science.
Prostacyclin is an anti-thrombotic hormone long considered to be derived from the vascular endothelium. However, the role of non-vascular sources for prostacyclin synthesis has not been systematically evaluated due to a lack of tools. Here we used cell-specific knockout mice and human tissues to show that lung, and other tissues, are powerful producers of prostacyclin independent of their vascular components. Instead, in mice and humans, lung prostacyclin synthesis is associated with fibroblasts. The fibroblast-derived prostaglandins enter the circulation and provide systemic anti-thrombotic protection. These observations define a new paradigm in prostacyclin biology in which fibroblast/non-vascular-derived prostacyclin works in parallel with prostaglandins produced by the endothelium to control cardiovascular health. These results may explain how local diseases of the lung and elsewhere result in cardiovascular risk.
Introduction:
Non-steroidal anti-inflammatory drugs (NSAIDs) work by inhibiting the enzyme cyclooxygenase (COX)2 but their use increases thrombotic risk. We have shown that COX2 inhibition increases plasma methylarginines ADMA and LNMMA in mice and man. Methylarginines are controlled in the kidney but circulate causing inhibition of anti-thrombotic vascular NO by competing with L-arginine for the active site of eNOS. However, the causative links between renal COX2 (which is expressed predominately in fibroblasts), methylarginines and thrombosis remain unproven.
Hypothesis:
Here we hypothesised that deletion of COX2 from fibroblasts would result in a renal-specific COX2-deficiency and be sufficient to increase methylarginine levels and drive vascular NO dysfunction and a pro-thrombotic phenotype.
Methods:
Fibroblast COX2-deficient mice were generated from Fsp1-Cre and Ptgs2
flox
strains. COX2 levels were measured by RT-qPCR, methylarginines by LC/MS/MS, vascular NO function as acetylcholine-induced dilation by myography and thrombosis in vivo after FeCl
3
-carotid injury.
Results:
Fibroblast COX2-deficient mice showed reduced COX2 expression in the renal medulla (Fig A) but not renal cortex, aorta, lung, colon, thymus or brain. This was associated with increased plasma ADMA and LNMMA levels (Fig B) and reduced NO-dependent dilatation of carotid arteries (Fig C). Fibroblast COX2-deficiency accelerated thrombosis after carotid artery injury which could be reversed by pre-treating animals with L-arginine (50mg/kg; 5 days) which displaces methylarginines from eNOS (Fig D).
Conclusions:
These data provide the first direct demonstration that renal COX2 regulates methylarginine levels to control systemic endothelial and thrombotic function. As such, they indicate that inhibition of renal COX2 contributes to the thrombotic risk seen in patients taking NSAIDs and suggest L-arginine supplementation as a potential rescue therapy to mitigate this.
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