Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Homocysteine (Hcy) metabolism involves multiple enzymes; however, tissue Hcy metabolism and its relevance to methylation remain unknown. Here, we established gene expression profiles of 8 Hcy metabolic and 12 methylation enzymes in 20 human and 19 mouse tissues through bioinformatic analysis using expression sequence tag clone counts in tissue cDNA libraries. We analyzed correlations between gene expression, Hcy, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM) levels, and SAM/SAH ratios in mouse tissues. Hcy metabolic and methylation enzymes were classified into two types. The expression of Type 1 enzymes positively correlated with tissue Hcy and SAH levels. These include cystathionine beta-synthase, cystathionine-gamma-lyase, paraxonase 1, 5,10-methylenetetrahydrofolate reductase, betaine:homocysteine methyltransferase, methionine adenosyltransferase, phosphatidylethanolamine N-methyltransferases and glycine N-methyltransferase. Type 2 enzyme expressions correlate with neither tissue Hcy nor SAH levels. These include SAH hydrolase, methionyl-tRNA synthase, 5-methyltetrahydrofolate:Hcy methyltransferase, S-adenosylmethionine decarboxylase, DNA methyltransferase 1/3a, isoprenylcysteine carboxyl methyltransferases, and histone-lysine N-methyltransferase. SAH is the only Hcy metabolite significantly correlated with Hcy levels and methylation enzyme expression. We established equations expressing combined effects of methylation enzymes on tissue SAH, SAM, and SAM/SAH ratios. Our study is the first to provide panoramic tissue gene expression profiles and mathematical models of tissue methylation regulation.

Summary Planar cell polarity (PCP) establishes polarity within an epithelial sheet. Defects in PCP are associated with developmental defects involving directional cell growth, including defects in kidney tubule elongation that lead to formation of kidney cysts. Given the strong association between kidney cyst formation and developmental biliary defects in patients and in animal models, we investigated the importance of PCP in biliary development. Here we report that in zebrafish, morpholino antisense oligonucleotide-mediated knockdown of PCP genes including prickle-1a (pk1a) led to developmental biliary abnormalities, as well as localization defects of the liver and other digestive organs. The defects in biliary development appear to be mediated via downstream PCP targets such as Rho kinase, Jun kinase (JNK), and both actin and microtubule components of the cytoskeleton. Knockdown of pk1a led to decreased expression of vhnf1, a homeodomain gene previously shown to be involved in biliary development and in kidney cyst formation; forced expression of vhnf1 mRNA led to rescue of the pk1a morphant phenotype. Our results demonstrate that PCP plays an important role in vertebrate biliary development, interacting with other factors known to be involved in biliary morphogenesis.

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A 71-year-old male with multivessel coronary artery disease who underwent bypass with saphenous vein grafts to a Marginal branch and distal RCA and LIMA to LAD in 1988, DM II, atrial fibrillation on Coumadin, TIA, obstructive sleep apnea and pulmonary hypertension was referred to our institution after extensive dyspnea evaluation with a diagnosis of constrictive pericarditis for pericardiectomy. He had normal left ventricular function, moderate mitral and tricuspid regurgitation. Coronary angiography revealed ostial LAD CTO, patent LIMA to mid LAD, second Marginal branch CTO with left-to-left collaterals and mid RCA CTO with left-to-right collaterals. Vein grafts to the Marginal branch and distal RCA were occluded. The pericardium was heavily calcified on CT of the chest. The LIMA was inadvertently injured leading to acute STEMI and ventricular fibrillation arrest treated with defibrillation once. Surgical repair was unsuccessful. A Graftmaster covered stent was successful deployed with restoration of TIMI III flow to the LAD territory. Pericardiectomy was completed via both the median resternotomy and left thoracotomy. Triple therapy with Aspirin, Clopidogrel, and Coumadin was initiated and maintained for 3 months without hemorrhagic or thrombotic complications. He has continued to do well in follow-up on Clopidogrel and Coumadin. K E Y W O R D S cardiomyopathy, coronary angiography, coronary bypass graft, percutaneous coronary intervention, resternotomy

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