Publications by authors named "Leroy C Joseph"

Article Synopsis
  • The study identifies the endoplasmic reticulum (ER) as a significant storage site for intracellular magnesium (Mg) and highlights the protein TMEM94 (ERMA) as a key player in its transport.* -
  • TMEM94 is characterized as a multi-pass transmembrane protein with structural similarities to P-type ATPases, featuring unique domains for nucleotide and phosphorylation interactions.* -
  • Research indicates that a specific tyrosine residue in TMEM94 is vital for Mg binding and function, with implications for cardiac health shown in both mice and human heart cells.*
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  • Some mutations in the Ca1.2 calcium channel gene lead to Timothy syndrome, a severe form of long QT syndrome, with no current effective treatments.
  • Targeting sigma non-opioid intracellular receptor 1 (SIGMAR1) can restore heart function in heart cells derived from patients with Timothy syndrome and other types of long QT syndrome.
  • The FDA-approved cough suppressant dextromethorphan acts as a SIGMAR1 agonist, improving cardiac function in Timothy syndrome models and suggesting a new therapeutic avenue for related inherited arrhythmias.
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  • This study investigates how the heart responds to a high-fat diet over four weeks in mice, measuring changes in metabolites and gene expression.
  • Findings indicated that a high-fat diet led to significant increases in certain fatty acid-related metabolites and changes in gene expression related to fatty acid utilization and antioxidant production.
  • The research also highlighted notable differences between male and female mice in terms of heart response to the high-fat diet, both in metabolite levels and gene expression patterns.
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  • Obesity and diabetes are linked to an increased risk of heart arrhythmias and sudden cardiac death, but the specific molecular mechanisms are not fully understood.
  • Researchers hypothesized that a high-fat diet (HFD) leads to mitochondrial dysfunction, contributing to ventricular arrhythmia, potentially through abnormal calcium handling in heart cells.
  • Experiments on mice indicated that deleting the mitochondrial calcium uniporter (Mcu) protects against HFD-induced heart issues, suggesting that targeting Mcu and the enzyme CaMKII could offer new treatments for arrhythmias related to metabolic disorders.
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  • A recent study by Petrosino et al. explores the impact of paracardial fat on metabolism and exercise, revealing a link between fat types and physical performance.
  • They found that older mice and those on a Western diet had lower levels of alcohol dehydrogenase 1 (ADH1) in their paracardial fat, which was also consistent in humans with obesity.
  • The study suggests that the function of paracardial fat could influence exercise by affecting metabolites in the body and highlights the potential for future research on interventions that might enhance recovery after heart surgery.
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  • Cardiac arrhythmias contribute to a significant number of deaths from cardiovascular diseases globally, with metabolic factors like obesity and diabetes increasing the risk.
  • Despite established links between high-fat diets and arrhythmias, the specific mechanisms behind this connection are still not fully understood, although oxidative stress is important.
  • The review explores metabolic changes caused by obesity and high-fat diets, and discusses possible treatments for arrhythmias, including the use of antioxidants.
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Ca signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca release both are increased, and association of RyR2 by FK506 binding protein 12.

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  • Sepsis-induced cardiomyopathy (SIC) leads to higher patient death rates, and currently, there are no targeted treatments available.
  • Research shows that the protein PKCδ plays a crucial role in causing abnormal calcium handling and mitochondrial dysfunction in the heart during sepsis.
  • Mice lacking PKCδ (knockout mice) exhibit better heart function and reduced mitochondrial damage compared to normal mice when exposed to sepsis, suggesting PKCδ could be a potential target for protection against cardiac issues in sepsis.
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  • Mutations in the lamin A/C gene (LMNA) lead to cardiomyopathy and disrupt how nuclei are positioned in fibroblasts.
  • Elevated ERK1/2 activity in cardiomyocytes from mutant mice affects nuclear positioning and can be targeted to alleviate disease symptoms.
  • The study identifies that ERK1/2 phosphorylates FHOD proteins, which impacts their function and is key in understanding how LMNA mutations contribute to cardiac issues.
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  • A high-saturated fat diet can increase the risk of arrhythmias and sudden cardiac death by affecting calcium homeostasis in the heart.
  • The research in mice showed that saturated fat activates the enzyme NOX2, leading to dangerous changes in heart rhythm and calcium handling, while polyunsaturated fats do not have this effect.
  • Inhibiting NOX2 can prevent the harmful heart effects of a high saturated fat diet, suggesting that NOX2 inhibitors might be a new treatment for heart rhythm issues related to excessive fat intake.
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Mutations in LMNA encoding lamin A/C and EMD encoding emerin cause cardiomyopathy and muscular dystrophy. Lmna null mice develop these disorders and have a lifespan of 7-8 weeks. Emd null mice show no overt pathology and have normal skeletal muscle but with regeneration defects.

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Cardiomyopathy frequently complicates sepsis and is associated with increased mortality. Increased cardiac oxidative stress and mitochondrial dysfunction have been observed during sepsis, but the mechanisms responsible for these abnormalities have not been determined. We hypothesized that NADPH oxidase 2 (NOX2) activation could be responsible for sepsis-induced oxidative stress and cardiomyopathy.

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Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy.

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Background: Diabetes and obesity are associated with an increased risk of arrhythmia and sudden cardiac death. Abnormal lipid accumulation is observed in cardiomyocytes of obese and diabetic patients, which may contribute to arrhythmia, but the mechanisms are poorly understood. A transgenic mouse model of cardiac lipid overload, the peroxisome proliferator-activated receptor-γ (PPARg) cardiac overexpression mouse, has long QT and increased ventricular ectopy.

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Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function.

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Pathologic cardiac hypertrophy can lead to heart failure, but the mechanisms involved are poorly understood. SERCA2 is critical for normal cardiac calcium handling and function and SERCA2 mRNA and protein levels are reduced by cardiac hypertrophy. We hypothesized that extracellular signal-regulated kinase (ERK) 1/2 activation during hypertrophy reduced SERCA2 transcription.

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We previously showed that striated muscle-selective depletion of lamina-associated polypeptide 1 (LAP1), an integral inner nuclear membrane protein, leads to profound muscular dystrophy with premature death in mice. As LAP1 is also depleted in hearts of these mice, we examined their cardiac phenotype. Striated muscle-selective LAP1 knockout mice display ventricular systolic dysfunction with abnormal induction of genes encoding cardiomyopathy related proteins.

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Cyclo[EKTOVNOGN] (AFPep), a cyclic 9-amino acid peptide derived from the active site of alpha-fetoprotein, has been shown to prevent carcinogen-induced mammary cancer in rats and inhibit the growth of ER(+) human breast cancer xenografts in mice. Recently, studies using replica exchange molecular dynamics predicted that the TOVN region of AFPep might form a dynamically stable putative Type I beta-turn, and thus be biologically active without additional amino acids. The studies presented in this paper were performed to determine whether TOVN and other small analogs of AFPep would inhibit estrogen-stimulated cancer growth and exhibit a broad effective-dose range.

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