Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. Several ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question.

The aberrant expression of transforming growth factor (TGF)-␤1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell motility and invasiveness. How EMT affects motility and invasion is not well understood. Here we report that HDAC6 is a novel modulator of TGF-␤1-induced EMT. HDAC6 is a microtubule-associated deacetylase that predominantly deacetylates nonhistone proteins, including ␣-tubulin, and regulates cell motility. We showed that TGF-␤1-induced EMT is accompanied by HDAC6-dependent deacetylation of ␣-tubulin. Importantly, inhibition of HDAC6 by small interfering RNA or the small molecule inhibitor tubacin attenuated the TGF-␤1-induced EMT markers, such as the aberrant expression of epithelial and mesenchymal peptides, as well as the formation of stress fibers. Reduced expression of HDAC6 also impaired the activation of SMAD3 in response to TGF-␤1. Conversely, inhibition of SMAD3 activation substantially impaired HDAC6-dependent deacetylation of ␣-tubulin as well as the expression of EMT markers. These findings reveal a novel function of HDAC6 in EMT by intercepting the TGF-␤-SMAD3 signaling cascade. Our results identify HDAC6 as a critical regulator of EMT and a potential therapeutic target against pathological EMT, a key event for tumor progression and fibrogenesis. Epithelial-mesenchymal transition (EMT)2 is defined as a series of events through which epithelial cells lose many of their epithelial characteristics and acquire properties that are typical of mesenchymal cells (1). Aberrant EMT has been well documented in chronic fibrosis in multiple organs and carcinoma progression. During progression to metastatic competence, carcinoma cells acquire mesenchymal gene expression patterns and properties through EMT, which results in coordinated alterations in adhesive properties, activation of proteolysis and motility, and competence to metastasize and establish secondary tumors at distant sites (1). Fibrosis is characterized by an increased number of myofibroblasts that deposit interstitial extracellular matrix. Mounting evidence indicates that a significant fraction of these myofibroblasts arise from the resident epithelial cells via EMT during renal and lung fibrogenesis (2-6).Family members of transforming growth factor (TGF)-␤ are among the most potent inducers of EMT in a variety of physiological and pathological contexts (7). The aberrant expression of TGF-␤1 is well documented in the tumor microenvironment and fibrotic lesions where TGF-␤1 is widely believed to promote tumor progression and tissue fibrosis (7). Several recent studies have elegantly demonstrated EMT of lung alveolar epithelial cells in biopsies from patients with idiopathic pulmonary fibrosis and in experimental pulmonary fibrosis (4,5,8). A host of evidence indicates an essential role for SMAD3 in the expression of a panel of EMT-related genes upon translocation into the nucleus (9). The molecular me...

There is increasing evidence that thiazolidinediones (TZDs), antidiabetic compounds that are synthetic ligands for the peroxisome proliferator-activated receptor ␥ (PPAR␥), have cardiovascular effects through as yet poorly defined mechanisms. We tested the effect of two TZD class drugs, rosiglitazone and pioglitazone, on human aortic smooth muscle cell (SMC) expression of insulin-like growth factor-1 receptor (IGF-1R). Both TZDs dose dependently up-regulated IGF-1R protein levels (rosiglitazone, 10 mol/liter, 67% increase, n ‫؍‬ 4, p < 0.01; pioglitazone, 10 mol/liter, 41% increase, n ‫؍‬ 4, p < 0.01) and increased IGF-1R signaling activity (36% increase in Akt phosphorylation). However, the endogenous PPAR␥ ligand, 15-deoxy-⌬ 12,14 -prostaglandin J 2 , dose dependently reduced IGF-1R (10 mol/liter, 80% decrease, n ‫؍‬ 4, p < 0.01), and overexpression of PPAR␥ using an adenovirus likewise reduced IGF-1R (50% decrease versus SMC infected with control adenovirus), suggesting a PPAR␥-independent action of TZDs. Thiazolidinediones (TZDs) 2 are insulin-sensitizing drugs used in patients with type 2 diabetes mellitus. Over the past decade, it has been suggested that TZDs could have anti-atherosclerotic effects (1-4), although human studies thus far have not been conclusive with regard to potential benefits (5-7), and one meta-analysis has suggested that rosiglitazone increased the risk of myocardial infarction (8). PPAR␥ agonists including TZDs have been found to reduce atherosclerosis in rodent models such as LDL receptor-null mice and apolipoprotein E-deficient mice (9 -12). TZDs inhibit proliferation and migration of cultured vascular smooth muscle cells (SMCs), which may contribute to their potential beneficial effect on atherogenesis (13-15).Insulin-like growth factor-1 (IGF-1), a growth factor found in the circulation and also produced locally in multiple tissues including the vasculature, has pleiotropic effects on vascular cells including SMCs (reviewed in Refs. 16 and 17). For instance, IGF-1 is a mitogen for vascular SMCs and could be involved in the restenotic process after mechanical vascular injury (18,19). Contrary to its mitogenic effect, it has also been reported that IGF-1 signaling is important for maintenance of the differentiated SMC phenotype (20, 21). IGF-1 is a potent survival factor for vascular SMCs. Thus, we have previously reported that oxidized low density lipoprotein (oxLDL), a highly pro-atherogenic lipoprotein present in circulation and in atherosclerotic plaques (22, 23), down-regulates IGF-1 in vascular cells (16,24), and overexpression of IGF-1 receptor (IGF-1R) prevents oxLDL-induced apoptosis of vascular cells (25). Intriguingly, IGF-1 and IGF-1R expression are reduced in areas of advanced human plaque staining positive for oxLDL (26,27), indicating a potential association between reduced IGF-1 function and the acellular phenotype of advanced plaques. Collectively, our studies suggest that IGF-1 serves as a survival factor for vascular SMCs, preventing SMC loss from atherosclerotic ...

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