Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr−/−) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.

The unprecedented outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO, with >34 million people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and with>1 million COVID-19-related deaths worldwide 1. COVID-19 can lead to a disease spectrum ranging from mild respiratory symptoms to acute respiratory distress syndrome (ARDS) and death 2-4. SARS-CoV-2 is now the third highly pathogenic and transmissible coronavirus identified in humans. Human coronaviruses were first dis covered in the 1960s 5 , but it was not until the 21st century that coronaviruses were recognized as major threats to public health. SARS-CoV 6-9 , Middle East respiratory syndrome coronavirus (MERS-CoV) 10 and SARS-CoV-2 all cause severe respiratory tract infections and have been associated with global pandemics. SARS-CoV was first reported in China in 2003 and infected >8,000 indivi duals, causing 774 deaths worldwide 11. A decade later, MERS was first reported in Saudi Arabia and infected >2,494 individuals and caused 858 deaths, with an extremely high death rate of 34% in part owing to the lack of effective therapies 12,13. SARS-CoV, MERS-CoV and SARS-CoV-2 belong to the Betacoronavirus genus, which is one of four genera of coronavirus 14. Phylogenetic analysis revealed that SARS-CoV-2 is closely related to two bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21 (with around 88% sequence identity), SARS-CoV (approximately 79% sequence identity) and MERS-CoV (approximately 50% sequence identity) 15. Homology modelling revealed that the receptor-binding domain structures in SARS-CoV and SARS-CoV-2 are similar, despite some amino acid variations 15. MERS-CoV infects human cells by binding to the dipeptidyl peptidase 4 receptor 16 , whereas both SARS-CoV 17 and SARS-CoV-2 (refs 18,19) use angiotensin-converting enzyme 2 (ACE2) as a receptor to infect cells. For SARS-CoV-2 infection, in addition to ACE2, one or more proteases including transmembrane protease serine 2 (TMPRSS2), basigin (also known as CD147) and potentially cathepsin B or cathepsin L are required 18,19. Acute respiratory distress syndrome (ArDs). A syndrome characterized by severe acute respiratory failure arising from inflammation and fluid build-up in the lungs.

U nlike most mature cells, smooth muscle cells (SMCs) are remarkably plastic and can dedifferentiate in response to environmental cues, 1,2 adding a layer of complexity to the regulation of gene expression. Although several transcription factors have been identified, a global mechanism that coordinately regulates SMC phenotype has yet to be uncovered. How SMC genes become silenced and then reactivated is unknown and is an area of intense investigation. Recent demonstration that the ten-eleven-translocation (TET) family of proteins is involved in DNA demethylation [3][4][5] prompted us to evaluate the role of the TET proteins in the modulation of SMC phenotype. Editorial see p 2002 Clinical Perspective on p 2057The TET proteins (TET1-TET3) are a recently discovered family of DNA demethylases. TET proteins oxidize 5-methylcytosine (5-mC) to generate 5-hydroxymethylcytosine (5-hmC), frequently called the sixth DNA base, in mammalian cells. 4,5 Through the base excision repair pathway, 5-hmC is then converted to unmethylated cytosine, leading to DNA demethylation and gene activation. [6][7][8] Therefore, the 5-hmC modification and the TET enzymes have emerged as key activators of gene expression. Studies of TET proteins and 5-hmC function in embryonic stem cells (ESCs) demonstrate that they play a major role in maintaining cellular pluripotency through the regulation of lineage-specific genes. 4,[9][10][11] In contrast to this role in ESC pluripotency, the TET proteins (and their 5-hmC products) have an opposing role in adult stem cells and somatic tissues. TET2 mutations have been described in several types of hematopoietic disorders in which the loss of TET2 has been shown to promote hematopoietic stem cell self-renewal.12 TET2 and 5-hmC levels are increased during neurogenesis, 13 and more recently, loss of TET2 and 5-hmC was demonstrated to be a key epigenetic event associated with Background-Smooth muscle cells (SMCs) are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis. Although key regulators of the SMC phenotype, including myocardin (MYOCD) and KLF4, have been identified, a unifying epigenetic mechanism that confers reversible SMC differentiation has not been reported. Methods and Results-Using human SMCs, human arterial tissue, and mouse models, we report that SMC plasticity is governed by the DNA-modifying enzyme ten-eleven translocation-2 (TET2). TET2 and its product, 5-hydroxymethylcytosine (5-hmC), are enriched in contractile SMCs but reduced in dedifferentiated SMCs. TET2 knockdown inhibits expression of key procontractile genes, including MYOCD and SRF, with concomitant transcriptional upregulation of KLF4. TET2 knockdown prevents rapamycin-induced SMC differentiation, whereas TET2 overexpression is sufficient to induce a contractile phenotype. TET2 overexpression also induces SMC gene expression in fibroblasts. Chromatin immunoprecipitation demonstrates that TET2 coordinately regul...

Vascular smooth muscle cell (VSMC) differentiation is an essential component of vascular development. These cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. VSMCs are not terminally differentiated and are able to modulate their phenotype in response to changing local environmental cues. There is clear evidence that alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of atherosclerosis and intimal hyperplasia, as well as in a variety of other major human diseases, including hypertension, asthma, and vascular aneurysms. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMCs, with particular focus on examination of signaling pathway that regulate this process.

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.