Homocysteine, a new cardiovascular risk factor, is also a powerful uremic toxin.
Homocystinuria, an inherited disease in which plasma levels of homocysteine are high, was discovered in the sixties and it soon became clear that the affected patients had striking features of generalized atherosclerosis. The most common causes of death were arterial and venous thrombosis, stroke, or myocardial infarction. Observations in this human model of hyperhomocysteinemia led to studies in the general population whose findings suggest - though not conclusively- that homocysteine is a cardiovascular risk factor. The same is true for patients with chronic renal failure who almost always have moderate to severe high blood homocysteine levels. Homocysteine accumulates in relation to the concentration of its precursor, S-adenosylhomocysteine, a powerful competitive transmethylation inhibitor. Inhibition of a methyltransferase required to repair damaged proteins has actually been detected in uremic patients' red blood cells. However, in view of the multiple, widespread metabolic roles of S-adenosylmethionine-dependent methyltransferases, in many organs and tissues including the vascular endothelium, hypomethylation is currently interpreted as one of homocysteine's most important mechanisms of action. Various biological compounds, including small molecules and nucleic acids, as well as proteins, which are involved in the pathophysiology of thrombosis and atherosclerosis, are all potential targets of hypomethylation. Epidemiological studies and experimental models tend to confirm that homocysteine is both a cardiovascular risk factor and a uremic toxin, acting through different mechanisms.
Perna
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AF
Department of Nephrology and Institute of Biochemistry of Macromolecules, S.U.N., School of Medicine, Naples, Italy. a-perna25@hotmail.com
Castaldo
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P
Ingrosso
D
D
De Santo
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NG
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000209:etiology*; D006710:Homocysteine / Q000502:physiology; D006712:Homocystinuria / Q000150:complications; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000503:physiopathology / Q000628:therapy; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000503:physiopathology; D012307:Risk Factors
D006710:Homocysteine