A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis.

All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B1 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

Vitamin A: a drug for prevention of restenosis/reocclusion after percutaneous coronary intervention?

The re-establishment of adequate blood flow in a vessel with a reduced lumen due to an atherosclerotic plaque by percutaneous vascular intervention is a well established procedure. However, the long-term outcome of such interventions is negatively influenced by the development of intimal hyperplasia/restenosis. Although extensively researched, this still represents a significant clinical problem. Retinoids, i.e. natural and synthetic derivates of vitamin A, represent a potential therapeutic compound, since they have been shown to influence the vast majority of processes that ultimately lead to reocclusion of the injured vessel. Retinoids exert their effects at the transcriptional level through their nuclear receptors. Targeting multiple processes, i.e. proliferation, migration, extracellular matrix composition and cell differentiation, as well as coagulation/fibrinolysis, should increase their future role in the prevention of restenosis. The purpose of this review is to summarize the diverse effects of retinoids on pathobiological and biological processes activated at sites of vascular injury with particular emphasis on intimal hyperplasia/restenosis after endovascular interventions.

Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells.

BACKGROUND: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene. METHODOLOGY/PRINCIPAL FINDINGS: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells. CONCLUSIONS/SIGNIFICANCE: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

Relationship of Loop Diuretic Dosing and Acute Changes in Renal Function during Hospitalization for Heart Failure.

BACKGROUND: Worsening renal function (WRF) during heart failure (HF) hospitalization is an accepted correlate of poor prognosis. Loop diuretics are increasingly being considered as a potential cause of worsened HF outcomes, perhaps via WRF. However, the magnitude of worsening in renal function attributable to loop diuretics has not been quantified. METHODS: This was a retrospective cohort study of patients who received care from a large health system and had a primary hospital discharge diagnosis of HF between Jan 1, 2000 and June 30, 2008. Patients with preexisting end-stage renal disease were excluded. Daily creatinine (Cr) measurements, furosemide dosing (only loop diuretic on hospital formulary), and radiocontrast dye studies were collected using administrative data. Day-to-day changes in Cr and MDRD estimated glomerular filtration (eGFR) were calculated. The first Cr or eGFR value during hospitalization or in the emergency department was considered baseline. Generalized estimating equations were used to test the association furosemide exposure over previous 2 days to the daily change in Cr and eGFR. Covariates included undergoing radiocontrast study, age, race, gender, and baseline Cr or eGFR. RESULTS: Among 6071 patients who met inclusion criteria there were a total of 20,645 observations. This cohort was 51% female, 68% African American, and baseline Cr was 1.36 mg/dl. Furosemide exposure was associated with an average daily increase in Cr of 0.021 mg/dL and decrease in eGFR of 0.72 ml/min/1.73m2 (per 100 mg furosemide daily, both p<0.001). Over a typical length of stay of 5 days this would amount to a Cr increase of 0.11 mg/dL or decrease in eGFR of 3.6 ml/min/1.73m2. Furosemide exposure accounted for only 0.4% and 0.1% of the variation in Cr and eGFR changes, respectively. Undergoing radiocontrast study, African American race, and higher age were associated with day-to-day creatinine increases (all p<0.01). Reanaysis after classifying furosemide exposure into low (<40mg/day), medium (40-100mg/day), and high (>100mg/day) and censoring patients-days after radiocontrast exposure did not significantly affect the magnitude of the worsening renal function. CONCLUSIONS: While loop diuretic exposure is statistically associated with WRF among hospitalized HF patients, the associated magnitude of renal function change is very small, and loop diuretics explain little of the variability in renal function during hospitalization. More important explanatory factors likely exist but remain unidentified.