A5038511603- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Cardiomyopathy and Myosin Studies
- Nitric Oxide and Endothelin Effects
- Ion Channels and Receptors
- Neuroscience and Neural Engineering
- Cardiovascular Function and Risk Factors
- Cardiovascular Effects of Exercise
- Muscle Physiology and Disorders
- Receptor Mechanisms and Signaling
- Heart Rate Variability and Autonomic Control
- Cardiac Arrhythmias and Treatments
- Hormonal Regulation and Hypertension
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Cardiac Fibrosis and Remodeling
- Cardiac Ischemia and Reperfusion
- Pulmonary Hypertension Research and Treatments
- Atrial Fibrillation Management and Outcomes
- Advanced Fluorescence Microscopy Techniques
- Sympathectomy and Hyperhidrosis Treatments
- Mitochondrial Function and Pathology
- Viral Infections and Immunology Research
- Signaling Pathways in Disease
- Protein Kinase Regulation and GTPase Signaling
- Biomarkers in Disease Mechanisms
University of Missouri
2015-2024
University of Missouri Hospital
2018-2021
Harry S. Truman Memorial Veterans' Hospital
2015
Tufts Medical Center
2015
Rush University Medical Center
2009-2012
University of Cincinnati
2010
Howard Hughes Medical Institute
2010
Cincinnati Children's Hospital Medical Center
2010
RIKEN Center for Brain Science
2010
University of California, Davis
2010
Rationale: Inositol 1,4,5-trisphosphate (IP 3 ) is a second messenger that regulates intracellular Ca 2+ release through IP receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein–coupled receptor (GPCR) signaling events lead to liberation, although its importance transducing hypertrophic response has not been established vivo. Objective: Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for...
Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption a Western diet (WD) containing excess fat (46%), sucrose (17.5%), high fructose corn syrup (17.5%) 16 weeks resulted aortic stiffening young female mice these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies testing whether WD-induced contributing to impairment,...
Inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)-dependent Ca(2+) signaling exerts positive inotropic, but also arrhythmogenic, effects on excitation-contraction coupling (ECC) in the atrial myocardium. The role of IP(3)R-dependent sarcoplasmic reticulum (SR) release ECC ventricular myocardium remains controversial. Here we investigated this pathway during isolated rabbit myocytes. Immunoblotting proteins from myocytes showed expression both type 2 and 3 IP(3)R at levels approximately...
Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden death. At the cellular level, Ca(2+) appears as cytosolic transients of alternating amplitude at regular beating frequency. multifactorial process but has been linked to disturbances in intracellular regulation. In atrial myocytes, we tested role voltage-gated current, sarcoplasmic reticulum (SR) load, restitution properties SR release occurrence pacing-induced alternans. Voltage-clamp experiments revealed that...
In heart failure (HF), arrhythmogenic Ca(2+) release and chronic depletion of the sarcoplasmic reticulum (SR) arise due to altered function ryanodine receptor (RyR) SR Ca(2+)-release channel. Dantrolene, a therapeutic agent used treat malignant hyperthermia associated with mutations skeletal muscle type 1 RyR (RyR1), has recently been suggested have effects on cardiac 2 (RyR2). this investigation, we tested hypothesis that dantrolene exerts antiarrhythmic inotropic HF ventricular myocytes by...
Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed WD or without Sp (1 mg·kg(-1)·day(-1)). After 4 mo on the WD, exhibited increased body weight visceral but similar blood pressures, compared control diet-fed mice....
Abstract The pig is recognized as a valuable model in biomedical research addition to its agricultural importance. Here we describe means for generating skeletal muscle efficiently from porcine induced pluripotent stem cells (piPSC) vitro thereby providing versatile platform applications ranging regenerative biology the ex vivo cultivation of meat. GSK3B inhibitor, CHIR99021 was employed suppress apoptosis, elicit WNT signaling events and drive naïve-type piPSC along mesoderm lineage, and,...
Abstract Aims Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel an osmotically-activated channel, and there limited information on the role of TRPV4 in cardiomyocytes. Our data show that protein expression increases cardiomyocytes aged heart. objective this study was to examine cardiomyocyte following hypoosmotic stress assess contribution cardiac contractility tissue damage...
The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile this patient population. This report provides evidence supporting hypothesis Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative cardio-metabolic failure. preclinical model displays a distinctive constellation findings are conceivably useful to extending understanding how pre-existing...
Aging increases reactive oxygen species (ROS) which can impair vascular function and contribute to brain injury. However, aging also promote resilience acute oxidative stress. Therefore, we tested the hypothesis that advanced age protects smooth muscle cells (SMCs) endothelial (ECs) of posterior cerebral arteries (PCAs; diameter, ∼80 μm) during exposure H
Conducted vasodilatation (CVD) reflects the initiation and rapid (>mm s(-1)) spread of hyperpolarization along endothelium into smooth muscle. The ion channels that initiate CVD remain unclear as do signalling pathways may complement electromechanical relaxation. Using isolated pressurized (75 mmHg; 37 degrees C) feed arteries (n=63; diameter: rest: 53 +/- 2 microm, maximal: 98 microm) from hamster retractor skeletal muscle, we investigated contribution calcium-activated potassium (KCa)...
Many physiological processes and pharmacological agents modulate the ryanodine receptor (RyR), primary sarcoplasmic reticulum (SR) Ca(2+) release channel in heart. However, how such modulations translate into functional effects during cardiac excitation-contraction coupling (ECC) is much less clear. Using a low dose (250 microM) of caffeine we sensitized RyR examined SR using dynamic measurements cytosolic ([Ca(2+)](i)) free within ([Ca(2+)](SR)). In field stimulated (1 Hz) rabbit...
An increase in tissue blood flow requires relaxation of smooth muscle cells along entire branches the resistance vasculature. Whereas spread hyperpolarization endothelium can coordinate cell relaxation, complementary signaling events have been implicated conduction vasodilation. We tested hypothesis that Ca(2+) waves propagate from to feed arteries exhibiting spontaneous vasomotor tone. Feed hamster retractor were isolated, pressurized 75 mmHg at 37 degrees C, and developed myogenic tone...
Background Cyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure ( HF ) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was manipulate cyclic monophosphate using the dipeptidyl‐peptidase 4 inhibitor saxagliptin phosphodiesterase tadalafil. We hypothesized that preservation cGMP would attenuate pathological improve left ventricular LV function. Methods Results assessed...
Calcium signalling in endothelial cells of resistance arteries is integral to blood flow regulation. Oxidative stress and dysfunction can prevail during advanced age we questioned how calcium may be affected. Intact endothelium was freshly isolated from superior epigastric Young (∼4 months) Old (∼24 male C57BL/6 mice. Under resting conditions, with no difference intracellular levels, hydrogen peroxide (H2 O2 ) availability ∼1/3 greater mice while vascular catalase activity reduced by nearly...
Abstract Aims Cardiomyocyte Ca2+ homoeostasis is altered with ageing and predisposes the heart to intolerance arrhythmia. Transient receptor potential vanilloid 4 (TRPV4) an osmotically activated cation channel expression in cardiomyocytes of aged heart. The objective this study was examine role TRPV4 handling arrhythmogenesis following ischaemia–reperfusion (I/R), a pathological scenario associated osmotic stress. Methods results membrane monitored prior I/R Langendorff-perfused hearts Aged...
To test the hypothesis that Ca(2+) responses to GPCR activation are coordinated between neighboring ECs of resistance arteries.EC tubes were freshly isolated from superior epigastric arteries C57BL/6 mice. Intercellular coupling was tested using microinjection propidium iodide. Following loading with fluo-4 dye, intracellular ACh imaged confocal microscopy.Cell-to-cell transfer iodide confirmed functional GJCs. A 1 μm stimulus evoked (9.8 ± 0.8/min, F/F(0) = 3.11 0.2) which pseudo-line-scan...
We recently developed a clinically relevant mini-swine model of heart failure with preserved ejection fraction (HFpEF), in which diastolic dysfunction was associated increased mitochondrial permeability transition (MPT). Early function is ATP and Ca2+-dependent, thus, we hypothesized chronic low doses cyclosporine (CsA) would preserve via inhibition MPT subsequently maintain normal cardiomyocyte Ca2+ handling contractile characteristics. Left ventricular cardiomyocytes were isolated from...
Abstract Aims Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated transient receptor potential vanilloid-4 (TRPV4) ion channel is expressed cardiomyocytes aged heart. This investigation tests hypothesis that TRPV4 alters Ca2+ handling and cardiac function response to increased ventricular preload cardiomyocyte stretch. Methods results Left maximal pressure (PMax) was monitored isolated working hearts Aged (24–27 months) mice following...
Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed following antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologics designed to target signaling the cardiomyocyte considered important for development heart failure. Under control a cardiomyocyte-specific promoter, AAV9sc.shmAKAP AAV9sc.RBD express small hairpin RNA perinuclear scaffold protein muscle A-kinase anchoring β (mAKAPβ) an...
Cardiac dysfunction in the aged heart reflects abnormalities cardiomyocyte Ca(2+) homeostasis including altered cycling through sarcoplasmic reticulum (SR). The ryanodine receptor antagonist dantrolene exerts antiarrhythmic effects by preventing spontaneous diastolic release from SR. We tested hypothesis that prevents without altering excitation-contraction coupling myocardium. Left ventricular cardiomyocytes isolated young (3 to 4 mo) and (24-26 C57BL/6 mice were loaded with indicator...
The Frank-Starling mechanism, whereby increased diastolic filling leads to cardiac output, depends on increasing the sarcomere length (Ls) of cardiomyocytes. Ventricular stiffness increases with advancing age, yet it remains unclear how such changes in compliance impact dynamics intact heart. We developed an isolated murine heart preparation monitor Ls as a function left ventricular pressure and tested hypothesis that lengthening response is impaired advanced age. Mouse hearts from young...