A5027900359- Connective tissue disorders research
- Aortic Disease and Treatment Approaches
- Cardiovascular Effects of Exercise
- Cardiovascular Function and Risk Factors
- Chemotherapy-induced cardiotoxicity and mitigation
- Aortic aneurysm repair treatments
- Cardiomyopathy and Myosin Studies
- Adipose Tissue and Metabolism
- Signaling Pathways in Disease
- Sports injuries and prevention
- Viral Infections and Immunology Research
- Cardiac Fibrosis and Remodeling
- Cardiac electrophysiology and arrhythmias
- Peptidase Inhibition and Analysis
- Mitochondrial Function and Pathology
- Cardiac Valve Diseases and Treatments
- Eosinophilic Disorders and Syndromes
- Cardiovascular and Diving-Related Complications
- Cardiovascular Issues in Pregnancy
- Hedgehog Signaling Pathway Studies
- Receptor Mechanisms and Signaling
- Oral and Maxillofacial Pathology
- Cardiac Ischemia and Reperfusion
- HER2/EGFR in Cancer Research
- Air Quality and Health Impacts
Johns Hopkins Medicine
2014-2023
Johns Hopkins University
2014-2023
Macquarie University
2015-2021
University of Alabama at Birmingham
2017
Daewoong Pharmaceutical (South Korea)
2017
University of Pennsylvania
2017
Emory University Hospital
2017
Johns Hopkins Hospital
2014
University of Baltimore
2010
Howard Hughes Medical Institute
2006
Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected MFS reflect excessive signaling transforming growth factor-beta (TGF-beta) family cytokines. We show aortic mouse model is associated with increased TGF-beta can be prevented antagonists such as TGF-beta-neutralizing antibody or angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular...
In the context of pancreatic cancer, metastasis remains most critical determinant resectability, and hence survival. The objective this study was to determine whether Hedgehog (Hh) signaling plays a role in cancer invasion because is likely have profound clinical implications. cell lines, Hh inhibition with cyclopamine resulted down-regulation snail up-regulation E-cadherin, consistent epithelial-to-mesenchymal transition, mirrored by striking reduction vitro invasive capacity (P < 0.0001)....
Mitral valve prolapse (MVP) is a common human phenotype, yet little known about the pathogenesis of this condition. MVP can occur in context genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations fibrillin-1. Fibrillin-1 contributes to regulated activation cytokine TGF-beta, and enhanced signaling consequence fibrillin-1 deficiency. We thus hypothesized that increased TGF-beta may contribute multisystem MFS, development...
Mitral valve prolapse (MVP) is a common human phenotype, yet little known about the pathogenesis of this condition. MVP can occur in context genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations fibrillin-1. Fibrillin-1 contributes to regulated activation cytokine TGF-β, and enhanced signaling consequence fibrillin-1 deficiency. We thus hypothesized that increased TGF-β may contribute multisystem MFS, development myxomatous...
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution its type 1 (AT1) and 2 (AT2) receptors remains unknown. We show that loss AT2 expression accelerates aberrant growth rupture aorta in a mouse model Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm mice; full protection required intact signaling. angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less...
Transforming growth factor–β promotes aortic aneurysm formation through activation of its “noncanonical” signaling pathway.
Chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is a major public health burden with no effective treatment. Emphysema also associated hypertension, can progress right ventricular failure, an important cause of morbidity mortality among patients COPD. Nuclear erythroid 2 p45 related factor-2 (Nrf2) redox-sensitive transcription factor that up-regulates battery antioxidative genes...
Loeys-Dietz syndrome (LDS) is a connective tissue disorder that characterized by high risk for aneurysm and dissection throughout the arterial tree phenotypically resembles Marfan syndrome. LDS caused heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result diminished signaling; however, aortic surgical samples from patients show evidence of paradoxically increased signaling. We generated 2 knockin mouse strains with Tgfbr1 Tgfbr2...
Background: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype not known. Methods: To define role inflammation in pathogenesis ACM, we characterized nuclear factor-κB signaling ACM models vitro and vivo cardiac myocytes from patient induced pluripotent stem cells. Results: Activation signaling, indicated by increased expression accumulation phospho-RelA/p65, occurred both an model (expression JUP 2157del2 neonatal...
Abstract Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype small-molecule antagonist cyclopamine had shown striking inhibition systemic metastases on in spontaneously metastatic orthotopic xenograft models. Cyclopamine is natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In present study, novel, orally bioavailable inhibitor,...
Background Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor upregulates battery antioxidative genes cytoprotective enzymes constitute cellular response to oxidative stress. Our previous studies have shown disruption mice (Nrf2−/−) causes increased susceptibility pulmonary emphysema, asthma sepsis due inflammation. Here we tested hypothesis Principal Findings To investigate role...
Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3β inhibitor, reverses disease phenotypes in zebrafish model ACM. Here, we show SB2 prevents myocyte injury cardiac dysfunction vivo two murine models ACM at baseline response to exercise. SB2-treated mice with desmosome mutations showed improvements ventricular ectopy fibrosis/inflammation...
Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O 2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of homeostasis. Mouse embryos lacking expression the -regulated HIF-1α subunit die at midgestation with severe malformations and vascular regression. Here we report that Hif1a f/f ;Tie2-Cre conditional knockout mice, which lack only in Tie2 + lineage cells, develop normally, but when subjected induced by transaortic...
Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections occur more frequently in men than women, but the reasons for sex difference remain unclear. The aim of this study was to assess whether gene changes heart during coxsackievirus B3 (CVB3) myocarditis male female BALB/c mice predicted worse DCM males. Although (P = 4.2 × 10(-5)) cardiac dilation 0.008) were males, there no replication heart. Fibrotic remodeling genes, such as tissue inhibitor metalloproteinase...
Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence their efficacy and safety in the disorder. Unexpectedly, mice treated CCBs show accelerated expansion, rupture, premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein C beta (PKCβ) as a critical mediator of this pathway...
The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors transforming growth factor-β (TGF-β) pathway. Using a mouse model Loeys-Dietz syndrome (LDS) that carries kinase-inactivating mutation TGF-β receptor I, we found effects this depend on lineage origin vascular smooth muscle cells (VSMCs). Secondary heart field–derived (SHF-derived), but not neighboring cardiac neural crest–derived (CNC-derived), VSMCs...
MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported nuclear encoded microRNA (miR-181c) present heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating gene expression.To investigate further how miR-181...
Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis progression to exercise-associated failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2 mut/mut), model ACM, die prematurely during swimming display myocardial dysfunction...
Dipankar Pramanik 1,2,* , Nathaniel R. Campbell Samarjit Das 2 Sonal Gupta 1,2 Venugopal Chenna Savita Bisht 5 Polina Sysa-Shah 3 Djahida Bedja Collins Karikari Charles Steenbergen Kathleen L. Gabrielson Amarnath Maitra 6,π and Anirban 1,2,4 1 The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland Department Pathology, Molecular Comparative Pathobiology, 4 Oncology, Internal Medicine 3, Center Integrated Oncology Cologne-Bonn,...