New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia.

Statins are the most effective drugs used worldwide to lower the serum LDL-C by inhibiting the rate-limiting step, HMG-CoA reductase, in cholesterol biosynthesis. Despite its prevalent use, statins are known to increase proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, hindering its efficiency. However, the underlying mechanisms remain elusive.

Large-scale microRNA functional high-throughput screening identifies miR-515-3p and miR-519e-3p as inducers of human cardiomyocyte proliferation.

Ischemic cardiomyopathy, driven by loss of cardiomyocytes and inadequate proliferative response, persists to be a major global health problem. Using a functional high-throughput screening, we assessed differential proliferative potential of 2019 miRNAs after transient hypoxia by transfecting both miR-inhibitor and miR-mimic libraries in human iPSC-CM. Whereas miR-inhibitors failed to enhance EdU uptake, overexpression of 28 miRNAs substantially induced proliferative activity in hiPSC-CM, with an overrepresentation of miRNAs belonging to the primate-specific C19MC-cluster.

Natural Killer T cells and the invariant subset promote atherosclerosis: A meta-analysis.

Aims: Natural Killer T (NKT) cells are reported to be both pro- and anti-atherosclerotic. With this meta-analysis, we evaluated the NKT population and their subsets in regulating the atherosclerotic disease in mice.

Main Methods: Eighteen pre-clinical (mice, n = 1276) and 6 clinical observational studies (humans, n = 116) met the eligibility criteria for inclusion.

Exploring the crosstalk between long non-coding RNAs and microRNAs to unravel potential prognostic and therapeutic biomarkers in β-thalassemia.

β-thalassemia is a prevalent monogenic disorder characterized by reduced or absent synthesis of the β-globin chain. Although great effort has been made to ameliorate the disease severity of β-thalassemic patients, progress has been stymied due to limited understanding of the detailed molecular mechanism of disease pathogenesis. Recently, non-coding RNAs have been established as key players in regulating various physiological and pathological processes.

Revisiting fetal hemoglobin inducers in beta-hemoglobinopathies: a review of natural products, conventional and combinatorial therapies.

Beta-hemoglobinopathies exhibit a heterogeneous clinical picture with varying degrees of clinical severity. Pertaining to the limited treatment options available, where blood transfusion still remains the commonest mode of treatment, pharmacological induction of fetal hemoglobin (HbF) has been a lucrative therapeutic intervention. Till now more than 70 different HbF inducers have been identified.

Proprotein convertase subtilisin/kexin type 9 (PCSK9): A potential multifaceted player in cancer.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel pharmacological target for hypercholesterolemia and associated cardiovascular diseases owing to its function to mediate the degradation of low-density lipoprotein receptor (LDLR). Findings over the past two decades have identified novel binding partners and cellular functions of PCSK9. Notably, PCSK9 is aberrantly expressed in a broad spectrum of cancers and apparently contributes to disease prognosis, indicating that PCSK9 could be a valuable cancer biomarker.

Inadvertent nucleotide sequence alterations during mutagenesis: highlighting the vulnerabilities in mouse transgenic technology.

In the last three decades, researchers have utilized genome engineering to alter the DNA sequence in the living cells of a plethora of organisms, ranging from plants, fishes, mice, to even humans. This has been conventionally achieved by using methodologies such as single nucleotide insertion/deletion in coding sequences, exon(s) deletion, mutations in the promoter region, introducing stop codon for protein truncation, and addition of foreign DNA for functional elucidation of genes. However, recent years have witnessed the advent of novel techniques that use programmable site-specific nucleases like CRISPR/Cas9, TALENs, ZFNs, Cre/loxP system, and gene trapping.

Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology.

Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases.

The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis.

Aims: Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight in Foxo3 effects is still limited. Here, we investigated the role of Foxo3 on natural killer (NK) cell responses and its effects in viral myocarditis.

Glutathione adducts on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic function as well as promote ischemic blood flow recovery.

The sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) is key to Ca(2+) homeostasis and is redox-regulated by reversible glutathione (GSH) adducts on the cysteine (C) 674 thiol that stimulate Ca(2+) uptake activity and endothelial cell angiogenic responses in vitro. We found that mouse hind limb muscle ischemia induced S-glutathione adducts on SERCA in both whole muscle tissue and endothelial cells. To determine the role of S-glutathiolation, we used a SERCA 2 C674S heterozygote knock-in (SKI) mouse lacking half the key thiol.

BRCA1 is a novel target to improve endothelial dysfunction and retard atherosclerosis.

Objective: BRCA1, a tumor suppressor gene implicated in breast and ovarian cancers, exerts multiple effects on DNA repair and affords resistance against cellular stress responses. We hypothesized that BRCA1 limits endothelial cell apoptosis and dysfunction, and via this mechanism attenuates atherosclerosis.

Methods: Loss and gain of function were achieved in cultured endothelial cells by silencing and overexpressing BRCA1, respectively.

Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1.

Objective: Alterations in cardiac energy and substrate metabolism play a critical role in the development and clinical course of heart failure. We hypothesized that the cardioprotective role of the breast cancer 1, early onset (BRCA1) gene might be mediated in part by alterations in cardiac bioenergetics.

Methods: We generated cardiomyocyte-specific BRCA1 homozygous and heterozygous knockout mice using the Cre-loxP technology and evaluated the key molecules and pathways involved in glucose metabolism, fatty acid metabolism, and mitochondrial bioenergetics.

MicroRNA-145 targeted therapy reduces atherosclerosis.

Background: MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability.

Methods And Results: Apolipoprotein E knockout mice (ApoE(-/-)) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks.

miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis.

Objective: Bone morphogenetic protein-2 (BMP-2) is a major regulator of aortic valve calcification. MicroRNAs (miRNAs) are essential post-transcriptional modulators of gene expression and miRNA-141 is a known repressor of BMP-2-mediated osteogenesis. We hypothesized that miRNA-141 is a key regulator of aortic valve calcification.

BRCA1 is an essential regulator of heart function and survival following myocardial infarction.

The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress.

BRCA2 protein deficiency exaggerates doxorubicin-induced cardiomyocyte apoptosis and cardiac failure.

The tumor suppressor breast cancer susceptibility gene 2 (BRCA2) plays an important role in the repair of DNA damage, and loss of BRCA2 predisposes carriers to breast and ovarian cancers. Doxorubicin (DOX) remains the cornerstone of chemotherapy in such individuals. However, it is often associated with cardiac failure, which once manifests carries a poor prognosis.

Herceptin, a recombinant humanized anti-ERBB2 monoclonal antibody, induces cardiomyocyte death.

P53 protein levels are elevated by trastuzumab and the biologically similar rat ERBB2/HER2/NEU antibody; and that this coincides with enhanced apoptosis, increased cleaved caspase-3 levels and diminished cardiac function. We also demonstrate that MDM2 may be a regulatory target of anti-ERBB2 thereby implicating the MDM2/p53 axis as a potential molecular component for the undesirable cardiac outcomes noted with trastuzumab. Finally, we show that these MDM2/p53-mediated events are independent of both the ERK1/2 and Akt systems.

Effects on duration of post-operative ischemia and patterns of blood flow recovery in different conditions of mouse hind limb ischemia.

Background: Current limitations to the experimentation on patients with peripheral arterial disease push the development of different preclinical strategies. We investigated both duration of ischemia and blood flow recovery in mouse models of partial femoral artery ligation.

Methods: Male BALB/c mice were used.

Adropin is a novel regulator of endothelial function.

Background: Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis and insulin resistance. Because vascular function and insulin sensitivity are closely related, we hypothesized that adropin may also exert direct effects on the endothelium.

Methods And Results: In vitro cell culture models were partnered with an in vivo murine injury model to determine the potential vascular effects of adropin.

Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages.

Altered macrophage kinetics is a pivotal mechanism of visceral obesity-induced inflammation and cardiometabolic risk. Because monocytes can differentiate into either proatherogenic M1 macrophages or anti-inflammatory M2 macrophages, approaches that limit M1 while promoting M2 differentiation represent a unique therapeutic strategy. We hypothesized that adiponectin may prime human monocytes toward the M2 phenotype.

Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction.

Background: In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction.

DNA damage repair and cardiovascular diseases.

DNA turnover through damage and repair is normal homeostatic process in viable cells. DNA damage induces sequential responses to either repair the damage or activate a programmed cell death process. Defects in this critical response to DNA damage underpin a wide array of human pathologies that include cancer predisposition, immune dysfunction, radiosensitivity, and neurodegeneration.

Visfatin activates eNOS via Akt and MAP kinases and improves endothelial cell function and angiogenesis in vitro and in vivo: translational implications for atherosclerosis.

Improving endothelial nitric oxide synthase (eNOS) bioactivity and endothelial function is important to limit native, vein graft, and transplant atherosclerosis. Visfatin, a NAD biosynthetic enzyme, regulates the activity of the cellular survival factor, Sirt1. We hypothesized that visfatin may improve eNOS expression, endothelial function, and postnatal angiogenesis.

Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis.

The endothelium plays a central role in the maintenance of vascular homeostasis. One of the main effectors of endothelial dysfunction is ANG II, and pharmacological approaches to limit ANG II bioactivity remain the cornerstone of cardiovascular therapeutics. Angiotensin converting enzyme-2 (ACE2) has been identified as a critical negative modulator of ANG II bioactivity, counterbalancing the effects of ACE in determining net tissue ANG II levels; however, the role of ACE2 in the vasculature remains unknown.

Conservation of 5'-upstream region of the FBN1 gene in primates.

Fibrillin-1 is a multifunctional extracellular protein encoded by the FBN1 gene. FBN1 is 237 kb in size and is located on chromosome 15q21. FBN1 mutations are known to cause Marfan syndrome and other fibrillinopathies.