A5051146510- Pulmonary Hypertension Research and Treatments
- RNA modifications and cancer
- Cardiac Fibrosis and Remodeling
- Cardiovascular Function and Risk Factors
- Cardiac electrophysiology and arrhythmias
- Phosphodiesterase function and regulation
- MicroRNA in disease regulation
- Drug Transport and Resistance Mechanisms
- Circular RNAs in diseases
- Cardiac Ischemia and Reperfusion
- Renin-Angiotensin System Studies
- Cardiac Structural Anomalies and Repair
- Ion Channels and Receptors
- Cancer-related gene regulation
- Signaling Pathways in Disease
- Tissue Engineering and Regenerative Medicine
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Congenital Heart Disease Studies
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Congenital heart defects research
- Receptor Mechanisms and Signaling
- Adenosine and Purinergic Signaling
- ATP Synthase and ATPases Research
- Neuropeptides and Animal Physiology
Virginia–Maryland College of Veterinary Medicine
2021-2025
Virginia Tech
2021-2025
Biomedical Research Institute
2021-2025
Carilion Clinic
2023-2025
Carilion Roanoke Memorial Hospital
2021-2025
German Centre for Cardiovascular Research
2013-2022
Icahn School of Medicine at Mount Sinai
2011-2021
Mount Sinai Hospital
2018-2021
Cardiovascular Research Center
2019-2020
Ronald Reagan UCLA Medical Center
2019
Background: Despite its functional importance in various fundamental bioprocesses, studies of N 6 -methyladenosine (m6A) the heart are lacking. Here, we show that FTO (fat mass and obesity-associated protein), an m6A demethylase, plays a critical role cardiac contractile function during homeostasis, remodeling, regeneration. Methods: We used clinical human samples, preclinical pig mouse models, primary cardiomyocyte cell cultures to study cardiomyocytes. modulated expression by using...
Background— Several microRNAs (miRs) have been shown to regulate gene expression in the heart, and dysregulation of their has linked cardiac disease. miR-378 is strongly expressed mammalian heart but so far studied predominantly cancer, which it regulates cell survival tumor growth. Methods Results— Here, we report tight control cardiomyocyte hypertrophy through miR-378. In isolated primary cardiomyocytes, was found be both necessary sufficient repress hypertrophy. Bioinformatic prediction...
Background: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored regulatory mechanisms enhance myocardial regeneration after infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an of glycolytic enzyme pyruvate kinase. role in proliferation, development, and cardiac unknown. Methods: We investigated effect cardiomyocytes through models loss...
Chronic cardiac stress induces pathologic hypertrophy and fibrosis of the myocardium. The microRNA-29 (miR-29) family has been found to prevent excess collagen expression in various organs, particularly through its function fibroblasts. Here, we show that miR-29 promotes myocytes overall dysfunction. In a mouse model pressure overload, global genetic deletion or antimiR-29 infusion prevents improves function. Targeted vivo also fibrosis, indicating dominates over non-myocyte cell types....
Cardiomyocytes use Ca2+ not only in excitation-contraction coupling but also as a signaling molecule promoting, for example, cardiac hypertrophy. It is largely unclear how triggers cardiomyocytes the presence of rapid and large fluctuations that occur during coupling. A potential route store-operated entry, drug-inducible mechanism requires stromal interaction 1 (STIM1). Store-operated entry can be induced cardiomyocytes, which prompted us to study STIM1-dependent with respect hypertrophy...
Myocardial ischemic disease is the major cause of death worldwide. After myocardial infarction, reperfusion infracted heart has been an important objective strategies to improve outcomes. However, cardiac ischemia/reperfusion (I/R) characterized by inflammation, arrhythmias, cardiomyocyte damage, and, at cellular level, disturbance in Ca 2+ and redox homeostasis. In this study, we sought determine how acute inflammatory response contributes injury homeostasis after ischemia. Using a rat...
Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with downregulation and progression PAH. Here, we investigated for first time role SIN3a (switch-independent 3a), a transcriptional regulator, epigenetic underlying PAH.We used lung samples from PAH patients non-PAH controls, preclinical mouse rat models, human smooth...
Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet underlying mechanism has remained enigmatic. Immunostaining sympathetic axons in optically cleared pineal glands from humans mice with disease revealed their substantial denervation compared controls. Spatial, single-cell, nuclear, bulk RNA sequencing traced this defect back to superior cervical ganglia (SCG), which responded accumulation inflammatory macrophages, fibrosis,...
The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or active efflux transporters, namely multidrug resistance-associated proteins (MRPs) MRP4 MRP5. To determine role MRP5 in cell signaling, we studied arterial SMCs, which effects cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during isolated human coronary artery SMCs following injury rat carotid arteries...
Multidrug resistance-associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies the role MRP4 development progression pulmonary hypertension (PAH), a severe vascular disease characterized by chronically elevated artery pressure accompanied remodeling small arteries prelude to right heart failure premature death. expression was increased from patients with idiopathic PAH well WT mice exposed hypoxic...
Increasing evidence suggests that microRNAs are intimately involved in the pathophysiology of heart failure. MicroRNA-22 (miR-22) is a muscle-enriched miRNA required for optimum cardiac gene transcription and adaptation to hemodynamic stress by pressure overload mice. Recent also miR-22 induces hypertrophic growth it oftentimes upregulated end stage However scope mRNA targets networks failure remained unclear. We analyzed transgenic mice with enhanced levels expression adult cardiomyocytes...
Myocardial fibrosis is associated with profound changes in ventricular architecture and geometry, resulting diminished cardiac function. There currently no information on the role of delta-like homologue 1 (Dlk1) regulation fibrotic response. Here, we investigated whether Dlk1 involved fibroblast-to-myofibroblast differentiation regulates myocardial explored molecular mechanism underpinning its effects this process. Using Dlk1-knockout mice adenoviral gene delivery, demonstrate that...
Acute stimulation of cardiac β-adrenoceptors is crucial to increasing function under stress; however, sustained β-adrenergic has been implicated in pathological myocardial remodeling and heart failure. Here, we have demonstrated that export cAMP from myocytes an intrinsic cardioprotective mechanism response stress. We report infusion into mice averted hypertrophy fibrosis a disease model pressure overload. The protective effect exogenous required adenosine receptor signaling. This...
Systemic inhibition of miR-21 has proven effective against myocardial fibrosis and dysfunction, while studies in cardiac myocytes suggested a protective role this cell type. Considering potential implications for therapy, we aimed to determine the fraction where exerts its pathological activity. We developed viral vector-based strategy gene targeting nonmyocyte cells vivo compared global myocyte-specific nonmyocyte-specific deletion chronic left ventricular pressure overload. Murine moloney...
Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as calcium sensor that regulated Ca(2+)-released activated channels in T cells. STIM1 found be upregulated serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) well neointima injured rat carotid arteries. Growth factors-induced proliferation significantly lower hCASMC transfected with siRNA than those scrambled...
Recent studies indicate that members of the multidrug-resistance protein (MRP) family belonging to ATP binding cassette type C (ABCC) membrane proteins extrude cyclic nucleotides from various cell types. This study aimed determine whether MRP regulate cardiac cAMP homeostasis. Here, we demonstrate MRP4 is predominant isoform present at plasma cardiacmyocytes and it mediates efflux in these cells. MRP4-deficient mice displayed enhanced myocyte formation, contractility, hypertrophy 9 mo age,...
Abstract Extracellular vesicles have emerged as promising nanocarriers for targeted drug delivery, but their therapeutic potential is limited by challenges related to administration route, loading, delivery and production at scale. Here, we report an innovative approach of peptides injured tissues using milk-derived small extracellular (mEVs) abundant, safe, orally administrable nanoplatform. We demonstrate that a sub-population mEVs naturally contain Connexin 43 (Cx43) its Carboxyl-Terminal...
Abstract Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden death. Here, we aim to identify microRNAs that regulate the human ask whether their manipulation allows for therapeutic modulation abnormalities. Quantitative analysis microRNA targetomes in myocytes identifies miR-365 as a primary repolarizing ion channels. Action recordings patient-specific induced pluripotent stem cell-derived show elevation significantly prolongs duration derived from...
Inhibition of pulmonary fibrosis (PF) by restoring sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a) expression using targeted gene therapy may be a potentially powerful new treatment approach for PF. Here, we found that SERCA2a was significantly decreased in lung samples from patients with PF and the bleomycin (BLM) mouse model In BLM-induced model, intratracheal aerosolized adeno-associated virus serotype 1 (AAV1) encoding human (AAV1.hSERCA2a) reduces associated vascular...