A5086108615- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Cardiovascular Function and Risk Factors
- Muscle Physiology and Disorders
- Viral Infections and Immunology Research
- Cardiac Fibrosis and Remodeling
- Signaling Pathways in Disease
- Congenital heart defects research
- Atrial Fibrillation Management and Outcomes
- Cardiac Ischemia and Reperfusion
- Receptor Mechanisms and Signaling
- Cardiac pacing and defibrillation studies
- Nitric Oxide and Endothelin Effects
- Adipose Tissue and Metabolism
- RNA Research and Splicing
- Cardiovascular and exercise physiology
- Cellular Mechanics and Interactions
- Cardiac Imaging and Diagnostics
- Mitochondrial Function and Pathology
- Tissue Engineering and Regenerative Medicine
- Protein Tyrosine Phosphatases
- Coronary Interventions and Diagnostics
- Renin-Angiotensin System Studies
University of Illinois Chicago
2015-2024
University of Illinois Urbana-Champaign
1999-2020
University of Arizona
2020
Texas A&M University – Kingsville
2020
Chulalongkorn University
2020
Indo-American Center
2019
Loyola University Chicago
2003-2015
Mayo Clinic
2015
University of Cincinnati
1996-2014
Cincinnati Children's Hospital Medical Center
1998-2014
The histologic diagnosis of Alzheimer9s disease (AD) might be aided if a more sensitive marker aberrant A4 amyloid protein deposition were available. We screened sample aged brains, using immunocytochemical methods to detect the deposition, and found that, in comparison with conventional techniques (silver impregnation Congo red), immunocytochemistry is allows an easier demarcation between "normal" "abnormal." If accepted as definitive for AD, then age-related prevalence AD increases...
Heart failure with preserved ejection fraction is 1 consequence of hypertension and caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) a known modulator Hypertension can lead to reduction in vascular NO, part because NO synthase (NOS) becomes uncoupled when oxidative depletion its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur the heart that NOS dysfunction.In hypertensive mouse model, dysfunction was accompanied oxidation, BH(4), NOS. Compared...
1 To assess the specific functions of cardiac isoform troponin I (cTnI), we produced transgenic mice that expressed slow skeletal (ssTnI) specifically in cardiomyocytes. Cardiomyocytes from these displayed quantitative replacement cTnI with transgene-encoded ssTnI. 2 The ssTnI were viable and fertile did not display increased mortality or detectable cardiovascular histopathology. They exhibited normal ventricular weights heart rates. 3 Permeabilized cardiomyocytes demonstrated an Ca2+...
We compared mechanical activity and Ca2+ transients of ventricular myocytes isolated from wild-type phospholamban (PLB)-deficient mouse hearts in control conditions during beta-adrenergic stimulation. Compared with controls, cells PLB-deficient showed 1) a 2-fold increase extent cell shortening, 2) 3-fold maximal shortening velocity, 3) 3.4-fold relengthening velocity. also demonstrated significant increases the peak amplitude fura 2 fluorescence ratio rates rising falling phases transient....
To investigate the functional consequences of a tropomyosin (TM) mutation associated with familial hypertrophic cardiomyopathy (FHC), we generated transgenic mice that express mutant alpha-TM in adult heart. The missense mutation, which results substitution asparagine for aspartic acid at amino position 175, occurs troponin T binding region TM. S1 nuclease mapping and Western blot analyses demonstrate increased expression 175 transgene different lines causes concomitant decrease levels...
We describe techniques for the isolation of Ca(2+)-tolerant myocytes from mouse (2 to 6 mo old) ventricle measurements mechanics contraction and microfluorimetry. Our approach involved special modifications existing methods that had been developed other species but were not successful when applied heart. Important features method are 1) a requirement careful timing (< 5 min) perfusion with nominally Ca(2+)-free solution; 2) solution containing specially selected batch collagenase in presence...
Graphical Abstract figure legend In the mammalian fetal (immature) heart, cardiomyocytes proliferate and can regenerate in a low-oxygen environment. lead up to after birth, major changes occur that result regeneration no longer being possible; however, timing of these events varies across species. Factors regulate this cardiomyocyte transition include nutrient oxygen availability, hormones microRNAs. An emerging field research is use biomarkers as non-invasive detection method for...
Background— Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1α (also called α-TM) predominant TM isoform in human hearts, precise composition remains unclear. Methods and Results— In this study, we quantified for first time levels isoforms heart, including a novel TPM1κ. By developing TPM1κ-specific antibody, found that TPM1κ protein expressed incorporated into organized myofibrils hearts its level...
Biased agonism of the angiotensin II receptor is known to promote cardiac contractility. Our laboratory indicated that these effects may be attributable changes at level myofilaments. However, signaling mechanisms remain unknown. Because a common finding in dilated cardiomyopathy reduction myofilament-Ca2+ response, we hypothesized β-arrestin would increase responsiveness model familial and improve function morphology.We treated cardiomyopathy-linked mouse expressing mutant tropomyosin...
Phospholamban ablation has been shown to result in significant increases cardiac contractile parameters and loss of beta-adrenergic stimulation. To determine whether partial reduction phospholamban levels is also associated with enhancement performance further examine the sensitivity system alterations levels, hearts from wild-type, phospholamban-heterozygous, phospholamban-deficient mice were studied parallel at subcellular, cellular, organ levels. The phospholamban-heterozygous expressed...
Abstract —Tropomyosin (TM) is an integral component of the thin filament in muscle fibers and involved regulating actin-myosin interactions. TM encoded by a family four alternatively spliced genes that display highly conserved nucleotide amino acid sequences. To assess functional developmental significance α-TM, murine α-TM gene was disrupted homologous recombination. Homozygous null mice are embryonic lethal, dying between 8 11.5 days post coitum. Mice heterozygous for viable reproduce...
Mutations in striated muscle alpha-tropomyosin (alpha-TM), an essential thin filament protein, cause both dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within are associated with the development of DCM humans: Glu40Lys Glu54Lys. To investigate functional consequences alpha-TM DCM, we generated transgenic mice that express mutant (Glu54Lys) adult heart. Results showed increase protein expression led to a reciprocal decrease endogenous...
Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and characterized maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca(2+) sensitivity, high susceptibility to sudden death. We tested the following hypothesis: correction of sensitivity can delay or prevent development HCM phenotype.We used an mouse model with E180G mutation α-tropomyosin (Tm180) that demonstrates severe dysfunction. To test our...
S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca 2+ sensitization and a slowing cross-bridge kinetics as result increased oxidative signaling. Although there is evidence for role stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism not well understood. We investigated whether myofilament modifications may be part responsible diastolic dysfunction HCM. administered N-acetylcysteine (NAC) 30 days to 1-mo-old wild-type mice transgenic...
The Frank-Starling law of the heart is a physiological phenomenon that describes an intrinsic property muscle in which increased cardiac filling leads to enhanced contractility. Identified more than century ago, relationship currently known involve length-dependent enhancement myofilament Ca2+ sensitivity. However, upstream molecular events link cellular stretch sensitivity are poorly understood. Because angiotensin II type 1 receptor (AT1R) and multifunctional transducer protein β-arrestin...
Apart from transplant, there are no satisfactory therapies for the severe depression in contractility familial dilated cardiomyopathy (DCM). Current heart failure treatments that act by increasing involve signaling cascades alter calcium homeostasis and induce arrhythmias. Omecamtiv mecarbil is a promising new inotropic agent developed may circumvent such limitations. direct cardiac myosin activator promotes prolongs strong myosin–actin binding conformation to increase duration of systolic...
We recently discovered pivotal contributions of stress kinase JNK2 (c-Jun N-terminal isoform 2) in increased risk atrial fibrillation through enhanced diastolic sarcoplasmic reticulum (SR) calcium (Ca2+) leak via RyR2 (ryanodine receptor 2). However, the role function SERCA2 (SR Ca2+-ATPase), essential maintaining SR Ca2+ content cycling during each heartbeat, is completely unknown.To test hypothesis that increases activity and exacerbates an arrhythmic leak-load relationship.We used...
Abstract —We compared the dynamics of contraction and relaxation single myocytes isolated from nontransgenic (NTG) mouse hearts transgenic (TG-β-Tm) that overexpress skeletal isoform tropomyosin (Tm). Compared with NTG controls, TG-β-Tm showed significantly reduced maximal rates no change in extent shortening. This result indicated depression determined is intrinsic to cells. To further investigate effect Tm switching on myofilament activity regulation, we measured force ATPase rate as...
1 Acidosis in cardiac muscle is associated with a decrease developed force. We hypothesized that slow skeletal troponin I (ssTnI), which expressed neonatal hearts, responsible for the observed decreased response to acidic conditions. To test this hypothesis directly, we used adult transgenic (TG) mice express ssTnI heart. Cardiac TnI (cTnI) was completely replaced by either FLAG epitope introduced into N-terminus (TG-ssTnI*) or without (TG-ssTnI) these mice. TG cTnI were also generated as...
Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, approved for treatment of multiple sclerosis. We hypothesize that modulation the by FTY720 would be therapeutic benefit sarcomere-linked HCM. Methods: treated mice an HCM-linked...