Cardiology Commons^™

Wnt Signaling Exerts An Antiproliferative Effect On Adult Cardiac Progenitor Cells Through Igfbp3., Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Frank Conyers, Michael Bauer, Annette Liao, Jian Guan, Dylan Crapps, Jung-Kyu Han, Hanhua Dong, Ahmad F Bayomy, Gabriel C Fine, Karen Westerman, Travis L Biechele, Randall T Moon, Thomas Force, Ronglih Liao

Center for Translational Medicine Faculty Papers

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.

OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.

METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical …

Advanced Glycation End Products Accelerate Ischemia/Reperfusion Injury Through Receptor Of Advanced End Product/Nitrative Thioredoxin Inactivation In Cardiac Microvascular Endothelial Cells., Yi Liu, Yanzhuo Ma, Rutao Wang, Chenhai Xia, Rongqing Zhang, Kun Lian, Ronghua Luan, Lu Sun, Lu Yang, Wayne B Lau, Haichang Wang, Ling Tao

Department of Emergency Medicine Faculty Papers

The advanced glycation end products (AGEs) are associated with increased cardiac endothelial injury. However, no causative link has been established between increased AGEs and enhanced endothelial injury after ischemia/reperfusion. More importantly, the molecular mechanisms by which AGEs may increase endothelial injury remain unknown. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and incubated with AGE-modified bovine serum albumin (BSA) or BSA. After AGE-BSA or BSA preculture, CMECs were subjected to simulated ischemia (SI)/reperfusion (R). AGE-BSA increased SI/R injury as evidenced by enhanced lactate dehydrogenase release and caspase-3 activity. Moreover, AGE-BSA significantly increased SI/R-induced oxidative/nitrative stress in CMECs (as measured …

Lipid Phosphate Phosphatase 3 Enables Efficient Thymic Egress, Béatrice Bréart, Willy D. Ramos-Perez, Alejandra Mendoza, Abdelghaffar K. Salous, Michael Gobert, Yong Huang, Ralf H. Adams, Juan J. Lafaille, Diana Escalante-Alcalde, Andrew J. Morris, Susan R. Schwab

Gill Heart & Vascular Institute Faculty Publications

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for …

Oxidative Stress Accumulates In Adipose Tissue During Aging And Inhibits Adipogenesis, Hannes M. Findeisen, Kevin J. Pearson, Florence Gizard, Yue Zhao, Hua Qing, Karrie L Jones, Dianne Cohn, Elizabeth B. Heywood, Rafael De Cabo, Dennis Bruemmer

Saha Cardiovascular Research Center Faculty Publications

Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at …

Paclitaxel Induces Thrombomodulin Downregulation In Human Aortic Endothelial Cells, Huang-Joe Wang, Te-Ling Lu, Haimei Huang, Huey-Chun Huang

The Texas Heart Institute Journal

Patients with paclitaxel-eluting stents are at risk of developing stent thrombosis upon premature discontinuation of dual antiplatelet therapy. In this study, we set out to clarify whether paclitaxel can modulate thrombomodulin expression in human aortic endothelial cells. Human aortic endothelial cells were stimulated with paclitaxel. Methoxyphenyl tetrazolium inner salt cell viability assay, Western blot analysis, real-time polymerase chain reaction, and immunohistochemical assay were performed. In human aortic endothelial cells, paclitaxel (10(-5) to 10(-9) mol/L) treatment for 13 hours caused significant cytotoxicity at drug concentrations greater than 10(-7) mol/L. Paclitaxel (10(-5) to 10(-9) mol/L) treatment for 5 hours downregulated thrombomodulin expression …

Micro-Ultrasonographic Imaging Of Atherosclerotic Progression And Correlation With Inflammatory Markers In Apolipoprotein-E Knockout Mice, Rong-Juan Li, Ya Yang, Yan-Hong Wang, Jin-Jie Xie, Li Song, Zheng Wang, Yao-Zhong Zhang, Yan-Wen Qin, Zhi-An Li, Xiao-Shan Zhang

The Texas Heart Institute Journal

We studied prospectively whether atherosclerotic progression in apolipoprotein-E knockout mice could be noninvasively and accurately measured by use of high-resolution ultrasonographic biomicroscopy. We examined the correlation between the ultrasonographic characterization of ascending aortic atherosclerotic plaque and plasma C-reactive protein, interleukin-1, and interleukin-6 levels in these mice.

In 4 age groups (8, 16, 24, and 32 wk) of 8 male knockout mice each (atherosclerotic groups) and age-matched male C57BL/6 mice (control groups), we used ultrasonographic biomicroscopy to measure maximal plaque thickness or intima-media thickness in the ascending aorta. We compared the findings with corresponding histologic measurements, and we measured plasma C-reactive …

Cd34-Positive Stem Cells In The Treatment Of Heart And Vascular Disease In Human Beings, Alexander R Mackie, Douglas W Losordo

The Texas Heart Institute Journal

Bone marrow-derived CD34(+) cells are a well-characterized population of stem cells that have traditionally been used clinically to reconstitute the hematopoietic system after radiation or chemotherapy. More recently, CD34(+) cells have also been shown to induce therapeutic angiogenesis in animal models of myocardial, peripheral, and cerebral ischemia. The mechanism by which CD34(+) cells promote therapeutic angiogenesis is not completely understood, although evidence supports both direct incorporation of the cells into the expanding vasculature and paracrine secretion of angiogenic growth factors that support the developing microvasculature. Phase I and phase II clinical trials have explored the usefulness of CD34(+) cells in …

Cardiac Dysfunction After Cancer Treatment, Michael S Ewer, Sandra M Swain, Daniela Cardinale, Anecita Fadol, Thomas M Suter

The Texas Heart Institute Journal

Onco-cardiology is an evolving discipline that requires the consideration of cardiotoxicity in preclinical, clinical,and therapeutic aspects of protocol development,treatment, and surveillance of patients who have undergone interventions using cardiotoxic agents. Only then can we foster new ways to maximize survival while keeping cardiac damage within acceptable limits. It is to this end that our working together has brought us to our present understanding. In the future, we may expect onco-cardiology to play an even greater role in the care of cancer patients.

Heterogeneity Of Left Ventricular Signal Characteristics In Response To Acute Vagal Stimulation During Ventricular Fibrillation In Dogs, Alireza Nazeri, Macarthur A Elayda, Lubomir Dragnev, Christopher M Frank, Jihong Qu, Valtino X Afonso, Abdi Rasekh, Mohammad Saeed, Jie Cheng, Mossaab Shuraih, Ali Massumi, Mehdi Razavi

The Texas Heart Institute Journal

Studies have shown that long-term vagal stimulation is protective against ventricular fibrillation; however, the effects of acute vagal stimulation during ventricular fibrillation in the normal heart have not been investigated. We examined the effects of acute vagal stimulation on ventricular fibrillation in a canine model. In 4 dogs, we induced 30-second periods of ventricular fibrillation by means of intraventricular pacing. During 2 of the 4 periods of fibrillation that we analyzed, vagal stimulation was delivered through electrodes in the caudal ends of the vagus nerves. Noncontact unipolar electrograms were recorded from 3 ventricular regions: the basal septum, apical septum, and …

Central Venous Pressure And Pulmonary Capillary Wedge Pressure, Tony S Ma, Biykem Bozkurt, David Paniagua, Biswajit Kar, Kumudha Ramasubbu, Carl F Rothe

The Texas Heart Institute Journal

Heart-failure phenotypes include pulmonary and systemic venous congestion. Traditional heart-failure classification systems include the Forrester hemodynamic subsets, which use 2 indices: pulmonary capillary wedge pressure (PCWP) and cardiac index. We hypothesized that changes in PCWP and central venous pressure (CVP), and in the phenotypes of heart failure, might be better evaluated by cardiovascular modeling. Therefore, we developed a lumped-parameter cardiovascular model and analyzed forms of heart failure in which the right and left ventricles failed disproportionately (discordant ventricular failure) versus equally (concordant failure). At least 10 modeling analyses were carried out to the equilibrium state. Acute discordant pump failure was …

A Dosing Study Of Bone Marrow Mononuclear Cells For Transendocardial Injection In A Pig Model Of Chronic Ischemic Heart Disease, Guilherme V Silva, Marlos R Fernandes, Cristiano O Cardoso, Ricardo R Sanz, Edie M Oliveira, Pilar Jimenez-Quevedo, Javier Lopez, Franca S Angeli, Yi Zheng, James T Willerson, Emerson C Perin

The Texas Heart Institute Journal

We studied the effect of the dose of bone marrow mononuclear cells, delivered via transendocardial injection, upon capillary density and fibrosis in pigs with chronic ischemic heart disease.

Pigs (n = 16) that had undergone ameroid constrictor placement (left circumflex coronary artery) to induce chronic ischemia were divided equally into 4 groups on the basis of bone marrow mononuclear cell dose: control (saline injection) and 50, 100, or 200 × 106 bone marrow mononuclear cells. Thirty days after ameroid placement, each pig received 13 transendocardial NOGA-guided injections. An implantable loop recorder monitored possible arrhythmias caused by cell transplantation. Thirty days …

Gsk-3alpha Directly Regulates Beta-Adrenergic Signaling And The Response Of The Heart To Hemodynamic Stress In Mice., Jibin Zhou, Hind Lal, Xiongwen Chen, Xiying Shang, Jianliang Song, Yingxin Li, Risto Kerkela, Bradley W Doble, Katrina Macaulay, Morgan Decaul, Walter J Koch, John Farber, James Woodgett, Erhe Gao, Thomas Force

Center for Translational Medicine Faculty Papers

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. …

Cardioprotection By Regular Ethanol Consumption: Potential Mechanisms And Clinical Application., Masami Miyamae, Kazuhiro Kaneda, Naochika Domae, Vincent M. Figueredo, M.D.

Division of Cardiology Faculty Papers

Epidemiological studies demonstrate that excessive drinking is associated with hypertension, cerebral bleeding and loss of cardiac contractility. Conversely, studies have shown that mortality rates for people who regularly drink ethanol in moderation are lower than in abstainers, primarily due to decreased fatal ischemic heart disease. Further, moderate ethanol consumers have lower rates of myocardial infarction compared with abstainers. These beneficial cardiac effects may be due to pleiotropic effects of ethanol on lipids, platelets, and fibrinolytic activity. During the past decade, studies conducted in several animal models have revealed that light to moderate regular ethanol consumption renders hearts more tolerant to …

Acute Memory Phase Of Sevoflurane Preconditioning Is Associated With Sustained Translocation Of Protein Kinase C-Alpha And Epsilon, But Not Delta, In Isolated Guinea Pig Hearts., Chika Okusa, Masami Miyamae, Shingo Sugioka, Kazuhiro Kaneda, Yoshitaka Inamura, Anna Onishi, Naochika Domae, Junichiro Kotani, Vincent M. Figueredo

Division of Cardiology Faculty Papers

BACKGROUND AND OBJECTIVE: Anaesthetic preconditioning (APC) exerts cardioprotective effects by reducing infarct size and improving recovery of contractile function after ischaemia-reperfusion. The interval between brief exposure to volatile anaesthetic and sustained ischaemia, the acute memory phase, is dependent on intracellular signalling mediating this cardioprotection. Intramyocyte translocation of protein kinase C (PKC) is known to be a key mediator in APC. We examined the relationship between the time frame of the acute memory phase of sevoflurane preconditioning and intramyocyte translocation of PKC-alpha, delta and epsilon to the particulate fraction. METHODS: Isolated perfused guinea pig hearts were subjected to 30 min ischaemia …

An Adrenal Beta-Arrestin 1-Mediated Signaling Pathway Underlies Angiotensin Ii-Induced Aldosterone Production In Vitro And In Vivo., Anastasios Lymperopoulos, Giuseppe Rengo, Carmela Zincarelli, Jihee Kim, Stephen Soltys, Walter J Koch

Center for Translational Medicine Faculty Papers

Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT(1)Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G(q/11)-proteins, to which the AT(1)R normally couples. Here, we describe a novel signaling pathway underlying this AT(1)R-dependent aldosterone production mediated by beta-arrestin-1 (betaarr1), a universal heptahelical receptor adapter/scaffolding protein. This pathway results in sustained ERK activation and subsequent …

Renin Inhibition Reduces Hypercholesterolemia-Induced Atherosclerosis In Mice, Hong Lu, Debra L. Rateri, David L. Feldman, Richard Charnigo, Akiyoshi Fukamizu, Junji Ishida, Elizabeth Grace Oesterling, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr^-/-) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in …

Sevoflurane Enhances Ethanol-Induced Cardiac Preconditioning Through Modulation Of Protein Kinase C, Mitochondrial Katp Channels, And Nitric Oxide Synthase, In Guinea Pig Hearts., Kazuhiro Kaneda, Masami Miyamae, Shingo Sugioka, Chika Okusa, Yoshitaka Inamura, Naochika Domae, Junichiro Kotani, Vincent M. Figueredo

Division of Cardiology Faculty Papers

BACKGROUND: Volatile anesthetics and regular ethanol consumption induce cardioprotection mimicking ischemic preconditioning. We investigated whether sevoflurane enhances ethanol preconditioning and whether inhibition of protein kinase C (PKC) and mitochondrial K(ATP) channels attenuated this enhanced cardioprotection. The effects of regular ethanol consumption on expression of inducible (iNOS) and endothelial (eNOS) nitric oxide synthase were determined. METHODS: Isolated perfused guinea pig hearts underwent 30-min global ischemia and 120-min reperfusion (Control: CTL). The ethanol group (EtOH) received 2.5% ethanol in their drinking water for 6 wk. Anesthetic preconditioning was elicited by 10-min exposure to sevoflurane (1 minimum alveolar anesthetic concentration; 2%) in ethanol …

Cardiac-Specific Elevations In Thyroid Hormone Enhance Contractility And Prevent Pressure Overload-Induced Cardiac Dysfunction, Maria G. Trivieri, Gavin Y. Oudit, Rajan Sah, Benoit-Giles Kerfant, Hui Sun, Anthony O. Gramolini, Yan Pan, Alan D. Wickenden, Walburga Croteau

Dartmouth Scholarship

Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and …

Probucol Prevents Early Coronary Heart Disease And Death In The High-Density Lipoprotein Receptor Sr-Bi/Apolipoprotein E Double Knockout Mouse, Anne Braun, Songwen Zhang, Helena E. Miettinen, Shamsah Ebrahim, Teresa M. Holm, Eliza Vasile, Mark J. Post

Dartmouth Scholarship

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment …