Publications by authors named "Rushita A Bagchi"

Bromodomain and extraterminal domain (BET) proteins, including BRD4, bind acetylated chromatin and coactivate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined.

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Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from key lysine residues on histone and nonhistone proteins and thereby regulate gene transcription. They have been implicated in several biological processes in both healthy and pathological settings. This review discusses the role of HDACs in multiple metabolically active tissues and highlights their contribution to the pathogenesis of tissue-specific maladaptation and diseases.

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Stimulation of adipocyte β-adrenergic receptors (β-ARs) induces expression of uncoupling protein 1 (UCP1), promoting nonshivering thermogenesis. Association of β-ARs with a lysine-myristoylated form of A kinase-anchoring protein 12 (AKAP12, also known as gravin-α) is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway.

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  • Stimulation of β-adrenergic receptors (β-ARs) in fat cells leads to increased expression of uncoupling protein 1 (UCP1), which helps generate heat without shivering.
  • The interaction of β-ARs with a specific form of the protein A-kinase anchoring protein 12 (AKAP12/gravin-α) is essential for activating UCP1, while HDAC11 can inhibit this pathway by removing myristoylation from gravin-α.
  • Deleting HDAC11 in fat cells or using the selective inhibitor FT895 enhances UCP1 expression and body temperature, even in cases where β-AR signaling is disrupted, suggesting that targeting HDAC11 could
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Aims: In response to pro-fibrotic signals, scleraxis regulates cardiac fibroblast activation in vitro via transcriptional control of key fibrosis genes such as collagen and fibronectin; however, its role in vivo is unknown. The present study assessed the impact of scleraxis loss on fibroblast activation, cardiac fibrosis, and dysfunction in pressure overload-induced heart failure.

Methods And Results: Scleraxis expression was upregulated in the hearts of non-ischemic dilated cardiomyopathy patients, and in mice subjected to pressure overload by transverse aortic constriction (TAC).

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Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation of reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, and induction of myofibroblast senescence. This pro-oxidant senescence reprogramming occurs in concert with conventional actions of UCP2 as an uncoupler of oxidative phosphorylation with dissipation of the mitochondrial membrane potential.

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  • - Myristoylation on lysine, unlike the well-known modification on glycine, plays a crucial but poorly understood role in protein function and localization, specifically for the protein gravin-α.
  • - Gravin-α is myristoylated on two lysine residues, which allows it to interact with histone deacetylase 11 (HDAC11) that can remove these modifications, impacting signaling pathways in adipocytes.
  • - This lysine myristoylation is essential for the proper functioning of β-adrenergic receptors, leading to the activation of PKA and promoting thermogenic gene expression, suggesting a potential therapeutic target in obesity management by inhibiting HDAC11.
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The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions.

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Acute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI.

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  • Acute kidney injury (AKI) can lead to serious problems in the lungs and increase the risk of death.
  • Researchers studied mice to see how AKI affects lung metabolism and found that it changes energy production and increases stress in the lungs.
  • The study suggests that AKI can harm the lungs in specific ways, which could help us understand why patients with AKI often have breathing issues.
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  • * In a study with mice that showed established DD, the HDAC inhibitor ITF2357/Givinostat was administered, and various methods were used to evaluate heart function, muscle mechanics, and fibrosis.
  • * The results indicated that HDAC inhibition effectively normalized DD without affecting blood pressure, reduced tissue stiffening, and prevented expansion of extracellular matrix proteins, which are linked to heart stiffness.
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  • Acute kidney injury (AKI) is linked to increased long-term heart-related health issues as shown by recent studies.
  • A 1-year study on male mice indicated that AKI results in ongoing problems with heart metabolism, leading to issues like high blood pressure and heart dysfunction.
  • Treatment with ITF2357 helped maintain normal heart function and blood pressure but did not prevent kidney scarring following AKI.
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Over the past two decades, it has become increasingly evident that microRNAs (miRNA) play a major role in human diseases such as cancer and cardiovascular diseases. Moreover, their easy detection in circulation has made them a tantalizing target for biomarkers of disease. This surge in interest has led to the accumulation of a vast amount of miRNA expression data, prediction tools, and repositories.

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Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF-β) inhibition efficiently promote reprogramming. However, the mechanisms by which TGF-β blockade promotes cardiac reprogramming remain unknown.

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  • Pulmonary arterial hypertension (PAH) is a serious lung disease that narrow the blood vessels, making it hard for the heart to pump blood and can lead to death.
  • Most treatments focus on relaxing these blood vessels, but they don't address other problems in the disease, so patients often still don’t feel well.
  • New research is looking into using treatments that target changes in DNA regulation, similar to those used for cancer, which could offer hope for better PAH therapies.
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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting millions worldwide. Currently, there are only four approved treatments for AD, which improve symptoms modestly. AD is believed to be caused by the formation of intercellular plaques and intracellular tangles in the brain, but thus far all new drugs which target these pathologies have failed clinical trials.

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  • BRD4 is identified as a key regulator in cardiac fibrosis, particularly through its role in TGF-β signaling that activates cardiac fibroblasts, the main cells involved in producing heart tissue's extracellular matrix.
  • Using techniques like RNA-sequencing and mass spectrometry, researchers showed that BRD4 can change the behavior of cardiac fibroblasts, prompting them to produce more extracellular matrix proteins in response to heart stress.
  • The study highlights that BRD4's activity is influenced by specific signals, causing it to relocate within the genome and interact with certain genes, suggesting targeted approaches for treating heart failure-associated fibrosis could be developed.
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Histone deacetylases (HDACs) regulate gene transcription by catalyzing the removal of acetyl groups from key lysine residues in nucleosomal histones and via the recruitment of other epigenetic regulators to DNA promoter/enhancer regions. Over the past two decades, HDACs have been implicated in multiple processes pertinent to cardiovascular and metabolic diseases, including cardiac hypertrophy and remodeling, fibrosis, calcium handling, inflammation and energy metabolism. The development of small molecule HDAC inhibitors and genetically modified loss- and gain-of-function mouse models has allowed interrogation of the roles of specific HDAC isoforms in these processes.

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Histone deacetylase 5 (HDAC5) and HDAC9 are class IIa HDACs that function as signal-responsive repressors of the epigenetic program for pathological cardiomyocyte hypertrophy. The conserved deacetylase domains of HDAC5 and HDAC9 are not required for inhibition of cardiac hypertrophy. Thus, the biological function of class IIa HDAC catalytic activity in the heart remains unknown.

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  • Acute Kidney Injury (AKI) can affect not just the kidneys but also the heart, causing serious problems.
  • In a study, researchers caused AKI in mice and looked at 124 substances in the heart over a week to see how they changed.
  • They found that 41% of these substances were altered, especially 24 hours after AKI, leading to less energy in the heart and issues with heart function.
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  • SSAT-1 is an important enzyme that helps cells grow, and a drug called amantadine can show how active this enzyme is in cancer.
  • Researchers found high levels of SSAT-1 in different types of tumors, like breast and lung cancer, and noticed cancer patients had more acetylated amantadine in their urine.
  • The study suggests that measuring SSAT-1 levels in tumors could help find certain cancers, and checking urine for acetylated amantadine might be an easy way to screen for cancer.
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Cardiac fibrosis, characterized by excessive accumulation of extracellular matrix, abolishes cardiac contractility, impairs cardiac function, and ultimately leads to heart failure. In recent years, significant evidence has emerged that supports the highly dynamic and responsive nature of the cardiac extracellular matrix. Although our knowledge of cardiac fibrosis has advanced tremendously over the past decade, there is still a lack of specific therapies owing to an incomplete understanding of the disease etiology and process.

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