Vitamin D metabolites influence the expression of various genes involved in calcium homeostasis, cell differentiation, and regulation of the immune system. Expression of these genes is mediated by the activation of the nuclear vitamin D receptor (VDR). Previous studies have shown that a hormonally active form of vitamin D, 1␣,25-dihydroxyvitamin D3, exerts anticoagulant effects in cultured monocytic cells. To clarify whether activation of VDR plays any antithrombotic actions in vivo, hemostatic/thrombogenic systems were examined in normocalcemic VDR knock-out (KO) mice on a high calcium diet and compared with wild type and hypocalcemic VDRKO mice that were fed a regular diet. Platelet aggregation was enhanced significantly in normocalcemic VDRKO mice compared with wild type and hypocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretions were reduced in hypocalcemic VDRKO mice, but not in normocalcemic VDRKO mice. Northern blot and RT-PCR analyses revealed that the gene expression of antithrombin in the liver as well as that of thrombomodulin in the aorta, liver and kidney was down-regulated in hypo-and normocalcemic VDRKO mice. Whereas tissue factor mRNA expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that activation of nuclear VDR elicits antithrombotic effects in vivo, and suggest that the VDR system may play a physiological role in the maintenance of antithrombotic homeostasis.

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-␤1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.Androgen exerts a variety of biological effects in many target organs, including male genitalia, brain, and skeletal tissues (1, 2). Most of these actions are mediated through the transcriptional control of particular sets of target genes by the nuclear androgen receptor (AR).1 AR is a ligand-inducible transcription factor that belongs to the nuclear receptor superfamily (3, 4). Upon hormone binding, AR is translocated from the cytosol into the nucleus where it binds specific promoter elements. A number of coregulators and/or coregulator complexes are then recruited to AR, which then activates or represses the transcription of various target genes (2, 3, 5-7). To clarify the physiological function of androgen via AR transcriptional regulation, we generated AR knock-out (ARKO) mice by means of the Cre-loxP system and have reported that ARKO male mice manifest late-onset obesity (8), high turnover osteopenia (9), and impaired brain masculinization (10).In addition to the classic target tissues of androgens, the AR gene is also expressed in mammalian cardiomyocytes, suggesting that androgens may play a role in the heart (11). In fact, Marsh and colleagues (11) have shown that androgens produce cardiac hypertrophy by a direct, receptor-specific mechanism. They also revealed that androgens regulate functional expression of an L-type calcium channel in isolated rat ventricular myocytes, leading to a modulation of cardiac performance in males (12). Li et a...

Background-Thrombin plays a crucial role in atherothrombotic changes. Because heparin cofactor II (HCII) inhibits thrombin actions after binding to dermatan sulfate at injured arterial walls, HCII may negatively regulate thrombin actions in vascular walls. We hypothesized that plasma HCII activity is a preventive factor against atherosclerotic changes, especially in elderly individuals who already have atherosclerotic vascular injuries. Methods and Results-Maximum plaque thickness (MPT) in the carotid artery was measured by ultrasonography in 306Japanese elderly individuals (154 men and 152 women; age, 40 to 91 years; 68.9Ϯ11.1 years, meanϮSD). The relevance of cardiovascular risk factors including plasma HCII activity to the severity of MPT was statistically evaluated. Plasma HCII activity decreased with age. Simple linear regression analysis after adjustments for age and sex showed that lipoprotein(a), glycosylated hemoglobin A1c, and presence of diabetes mellitus significantly contributed to an increase in MPT values (rϭ0.119, PϽ0.05; rϭ0.196, PϽ0.001; and rϭ0.227, PϽ0.0001, respectively). In contrast, high-density lipoprotein (HDL) cholesterol and HCII activity were negatively correlated with MPT values (rϭϪ0.117, PϽ0.05, and rϭϪ0.202, PϽ0.0005, respectively). Multiple regression analysis revealed that plasma HCII activity and HDL cholesterol independently contributed to the suppression of MPT values and that the antiatherogenic contribution of HCII activity was stronger than that of HDL cholesterol (PϽ0.001 and PϽ0.05, respectively). Conclusions-These results suggest that HCII can be a novel and independent antiatherogenic factor. Moreover, HCII is a stronger predictive factor than HDL cholesterol against carotid atherosclerosis in elderly individuals. (Circulation.

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