Diabetes mellitus (DM) is a complex metabolic disorder arising from lack of insulin production or insulin resistance (Diagnosis and classification of diabetes mellitus, 2007). DM is a leading cause of morbidity and mortality in the developed world, particularly from vascular complications such as atherothrombosis in the coronary vessels. Aldose reductase (AR; ALR2; EC 1.1.1.21), a key enzyme in the polyol pathway, catalyzes nicotinamide adenosine dinucleotide phosphate-dependent reduction of glucose to sorbitol, leading to excessive accumulation of intracellular reactive oxygen species (ROS) in various tissues of DM including the heart, vasculature, neurons, eyes, and kidneys. As an example, hyperglycemia through such polyol pathway induced oxidative stress, may have dual heart actions, on coronary blood vessel (atherothrombosis) and myocardium (heart failure) leading to severe morbidity and mortality (reviewed in Heather and Clarke, 2011). In cells cultured under high glucose conditions, many studies have demonstrated similar AR-dependent increases in ROS production, confirming AR as an important factor for the pathogenesis of many diabetic complications. Moreover, recent studies have shown that AR inhibitors may be able to prevent or delay the onset of cardiovascular complications such as ischemia/reperfusion injury, atherosclerosis, and atherothrombosis. In this review, we will focus on describing pivotal roles of AR in the pathogenesis of cardiovascular diseases as well as other diabetic complications, and the potential use of AR inhibitors as an emerging therapeutic strategy in preventing DM complications.

Atherosclerotic cardiovascular disease is considered as the leading cause of mortality and morbidity worldwide. Accumulating evidence supports an important role for long noncoding RNA (lncRNA) in the pathogenesis of atherosclerosis. Nevertheless, the role of lncRNA in atherosclerosis-associated vascular dysfunction and the underlying mechanism remain elusive. Here, using microarray analysis, we identified a novel lncRNA RP11-714G18.1 with significant reduced expression in human advanced atherosclerotic plaque tissues. We demonstrated in both human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that RP11-714G18.1 impaired cell migration, reduced the adhesion of ECs to monocytes, suppressed the neoangiogenesis, decreased apoptosis of VSMCs and promoted nitric oxide production. Mechanistically, RP11-714G18.1 could directly bind to its nearby gene LRP2BP and increased the expression of LRP2BP. Moreover, we showed that RP11-714G18.1 impaired cell migration through LRP2BP-mediated downregulation of matrix metalloproteinase (MMP)1 in both ECs and VSMCs. In atherosclerotic patients, the serum levels of LRP2BP were positively correlated with high-density lipoprotein cholesterol, but negatively correlated with cardiac troponin I. Our study suggests that RP11-714G18.1 may play an athero-protective role by inhibiting vascular cell migration via RP11-714G18.1/LRP2BP/MMP1 signaling pathway, and targeting the pathway may provide new therapeutic approaches for atherosclerosis.

Objective Drug-eluting stent delivery of mTORC1 inhibitors is highly effective in preventing intimal hyperplasia following coronary revascularization, but adverse effects limit utility for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell (SMC) differentiation in an AKT2-dependent manner in vitro. Here we investigate the roles of AKT isoforms in intimal hyperplasia. Approach and Results We found that germline or smooth muscle-specific deletion of Akt2 resulted in more severe intimal hyperplasia compared to control mice after arterial denudation injury. Conversely, smooth muscle-specific Akt1 knockout prevented intimal hyperplasia, while germline Akt1 deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild type mice but had no therapeutic benefit in Akt2 knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in SMC proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced MYOCD mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4, inhibiting its binding to the MYOCD promoter. Conclusions Our data reveal opposing roles for AKT isoforms in SMC remodeling. AKT2 is required for rapamycin’s therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of myocardin (MYOCD) via FOXO4. Because AKT2 signaling is impaired in diabetes, this work has important implications for rapamycin therapy, particularly in diabetic patients.

We thank Drs Li and Yu for their enthusiastic comments on our recent work 1 identifying Ten-Eleven-Translocation 2 (TET2) as a novel epigenetic master regulator of smooth muscle cell (SMC) phenotype. We also appreciate their highlighting the implications of our study regarding a role for TET2 in cellular reprogramming. We concur that this is an exciting example of a single epigenetic agent promoting the SMC phenotype in fibroblasts, but we hypothesize that TET2 in combination with other regulatory factors may be even more potent in conversion of non-SMC to the SMC lineage. We are currently working to identify these cofactors.Extensive work from many labs over the past 30 years has revealed the importance of epigenetic modifications, including changes in DNA methylation and histone acetylation, in cellular reprogramming and transdifferentiation. In one of the earliest demonstrations, the DNA methylation inhibitor 5-azacytidine could revert 3T3 and C3H10T1/2 cells to a more pluripotent state that then permitted cellular differentiation into the bone, muscle, and adipogenic lineages. Similarly, inhibition of histone deacetylation and DNA methylation has been shown to improve reprogramming efficiency of somatic cell nuclear transfer, 3 as well as in the production of induced pluripotent stem cells after ectopic expression of defined factors in fibroblasts. 4 The actions of the TET enzymes indeed contribute to DNA demethylation and thus may also contribute to the reprogramming process. Notably, we concur with Drs Li and Yu that generation of 5hmC as a stable epigenetic mark could contribute to reprogramming in addition to acting as an intermediate leading to demethylation. Indeed, our work unexpectedly revealed the stable presence of 5hmC in differentiated SMC in vivo. 1 We reported that ectopic expression of TET2 is able to convert MRC5 fibroblasts into the smooth muscle lineage as demonstrated by the robust upregulation of SMC markers including SMA and MYH11. Interestingly, TET2 overexpression was only able to partially convert endothelial cells to the smooth muscle lineage.1 The mechanisms underlying the cell type-specific differences in TET2-mediated reprogramming efficiency remain to be explored. We speculate that the embryonic origin of MRC5, a cell line commonly used for reprogramming studies, may confer a greater plasticity that can therefore be more readily differentiated into multiple lineages compared with the more fully differentiated adult endothelial cells. Our results are reminiscent of those of Cordes and colleagues, 5 who reported that ectopic miR145 is inefficient to induce SMC phenotype in C3H10T1/2 embryonic fibroblasts, but is highly potent to induce differentiation in the more pluripotent Joma1.3 neural crest stem cell line.We are pursuing new studies to further address the roles of TET2 in vascular disease. The fact that TET2 overexpression does not convert endothelial cells to the SMC lineage suggests potential for TET2-based therapies for vascular diseases. Further exploration of the role for...

No abstract

No abstract

No abstract

No abstract