Murine models of hyperhomocysteinemia and their vascular phenotypes

Abstract

Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine beta-synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.

Figure 1

Approaches to produce hyperhomocysteinemia in mice based on the metabolic pathways of homocysteine. Homocysteine is generated in the cytoplasm as an intermediate metabolite of the methionine cycle. Once formed, homocysteine can be metabolized through one of three pathways. First, homocysteine can be metabolized to cystathionine by cystathionine β-synthase (CBS). This reaction requires vitamin B6 as a cofactor. Second, homocysteine can be remethylated to methionine by methionine synthase (MS) in a reaction that requires vitamin B12. This reaction utilizes a methyl group from 5-methyl tetrahydrofolate (THF) and thus serves to link the methionine cycle with the folate cycle. 5-methyl THF is derived from the activity of methylene tetrahydrofolate reductase (MTHFR). Methionine synthase reductase (MSR) is required to maintain MS in its active conformation. Third, in the liver and kidney homocysteine can be remethylated to methionine by betaine:homocysteine methyltransferase (BHMT). This reaction uses betaine, which is derived from choline, as a methyl donor. Hyperhomocysteinemia can be induced in mice by: 1) dietary administration of methionine or homocysteine, 2) dietary deficiency of folate, vitamin B6, vitamin B12 or choline (blue), 3) genetic deficiency of CBS, MTHFR, MS or MSR, or 4) pharmacological inhibition of BHMT (green).