A5054755473- Ubiquitin and proteasome pathways
- Mitochondrial Function and Pathology
- Endoplasmic Reticulum Stress and Disease
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Autophagy in Disease and Therapy
- Parathyroid Disorders and Treatments
- PI3K/AKT/mTOR signaling in cancer
- Cardiomyopathy and Myosin Studies
- Nitric Oxide and Endothelin Effects
- Peptidase Inhibition and Analysis
- Phosphodiesterase function and regulation
- Receptor Mechanisms and Signaling
- Polyamine Metabolism and Applications
- Heart Failure Treatment and Management
- Cardiovascular Function and Risk Factors
- Cardiac Fibrosis and Remodeling
- Glycosylation and Glycoproteins Research
- Tuberous Sclerosis Complex Research
- Galectins and Cancer Biology
- Mast cells and histamine
- Cardiac electrophysiology and arrhythmias
- Ion Channels and Receptors
- Adipose Tissue and Metabolism
- Signaling Pathways in Disease
- Cardiac Ischemia and Reperfusion
Johns Hopkins University
2016-2025
Johns Hopkins Medicine
2013-2025
Johns Hopkins Hospital
2024
Kumamoto University
2018
University of South Dakota
2008-2015
MARK Resources (United States)
2011-2015
University of Würzburg
2014
Augusta University
2013
University of Rochester Medical Center
2011
Yale University
2011
Recent studies suggest an important role of autophagy in protection against αB-crystallin-based (CryAB(R120G)) desmin-related cardiomyopathies (DRC), but this has not been demonstrated a different model cardiac proteinopathy. Mechanisms underlying the response cardiomyocytes to proteotoxic stress remain incompletely understood.Our first objective was determine whether and how autophagic activity is changed mouse desminopathy. We also investigated p62 protein quality control...
Background— Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role their pathogenesis. The regulation proteasome function poorly understood, hindering the development effective strategies to improve function. Methods Results— Protein kinase G (PKG) was manipulated genetically pharmacologically cultured cardiomyocytes. Activation PKG increased peptidase activities, facilitated proteasome-mediated degradation surrogate...
Significance Transient receptor potential canonical 6 (TRPC6) is an important mediator of pathological hypertrophy and fibrosis, contributing to renal cardiac disease. However, no selective TRPC6 inhibitor with in vivo efficacy has been developed tested determine if nongenetic channel suppression ameliorates disease intact animals. We orally bioavailable TRPC6-specific inhibitor, BI 749327, revealing its capacity improve function reduce chamber dilation fibrosis the context abnormal...
Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles mast (MCs) in remodeling. Because mutations affect multiple types of both immune nonimmune origin, we addressed the impact MCs on function MI, c-Kit-independent MC-deficient (Cpa3(Cre/+)) mice. In response to...
Abstract Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators reprogramming in cancer, though their potential role abnormal heart growth fibrosis remains little understood. Here, we investigate gain loss function an H3K9me2 specific demethylase, Kdm3a , show it...
Background— Autophagy is essential to intracellular homeostasis and involved in the pathophysiology of a variety diseases. Mechanisms regulating selective autophagy remain poorly understood. The COP9 signalosome (CSN) conserved protein complex consisting 8 subunits (CSN1 through CSN8), known regulate ubiquitin-proteasome system. However, it unknown whether CSN plays role autophagy. Methods Results— Marked increases LC3-II p62 proteins were observed on Csn8 depletion cardiomyocytes mouse...
The cGMP-dependent protein kinase-1α (PKG1α) transduces NO and natriuretic peptide signaling; therefore, PKG1α activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress efficacy of pathway underlie variable clinical results. also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, impact oxidation on myocardial regulation is unknown. Here, we demonstrated that...
Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with significant mortality. The Val122Ile variant, highly prevalent in Black patients, portends poorer survival compared other ATTR-CM subtypes. Although biologically more aggressive, the contribution of race and socioeconomic status (SES) to disease outcomes patients undefined. aim this study was evaluate impact SES on clinical ATTR-CM. Patients who received care at Johns Hopkins Hospital between 2006 2022 were included. assessed...
Rationale: The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis is activated following ischemia reperfusion (IR) injury by ischemic preconditioning (IPC). However, studies vary as to whether this activation beneficial or detrimental, its influence on after IR little reported. A limitation prior investigations their use broad gain/loss function, mostly applied before stress. This can be circumvented regulating one serine (S1365) TSC2 (tuberous...
Normal endothelial cell dependent vascular smooth muscle function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and relaxation. NO bioavailability impaired in high glucose (HG). We tested hypothesis that sGC sensitizer vericiguat reverses HG-mediated decreased two experimental models, human aortic cells (HVSMCs) isolated mouse...
Rationale: GSK-3β (glycogen synthase kinase 3β) is a multifunctional and constitutively active known to regulate myriad of cellular processes. The primary mechanism its function through phosphorylation-dependent inhibition at serine-9 residue. Emerging evidence indicates that there may be alternative mechanisms control for certain functions. Objectives: Here, we sought understand the role protein S -nitrosylation (SNO) on GSK-3β. SNO-dependent modulation localization ability phosphorylate...
Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus Hsc70-interacting protein (CHIP) is an important regulator proteostasis in cells, having E3-ligase and chaperone functions often directing damaged towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated turnover markedly post-translationally...
Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy dysfunction increases autophagy. oxidation cysteine-42 is also induced these stressors, which blunts its cardioprotective effects.
Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TG AC8 ) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and output) for up a year without signs failure or excessive mortality. Here, we show classical hypertrophy markers were absent TG , that total left ventricular (LV) mass was not increased: reduced LV cavity volume encased by thicker walls harboring number small myocytes, network...
Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO·), confers unique physiological effects including vasorelaxation enhanced cardiac contractility. These features have spawned current pharmaceutical development HNO donors as heart failure therapeutics. interacts with selective redox sensitive cysteines to effect signaling but is also proposed activate soluble guanylate cyclase (sGC) in vitro induce vasodilation potentially enhance Here, we tested whether sGC stimulation...