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Kassandra S Thomson, Guy L Odom, Charles E Murry, Gregory G Mahairas, Farid Moussavi-Harami, Sam L Teichman, Xiaolan Chen, Stephen D Hauschka, Jeffrey S Chamberlain, Michael Regnier
Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms, and improve functional capacity and quality of life. We discovered small amounts of 2-deoxy-ATP (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin crossbridge cycling with greater force generation during each contraction...
December 2016: JACC. Basic to Translational Science
Sarah G Nowakowski, Michael Regnier, Valerie Daggett
Myosin activation is a viable approach to treat systolic heart failure. We previously demonstrated that striated muscle myosin is a promiscuous ATPase that can use most nucleoside triphosphates as energy substrates for contraction. When 2-deoxy ATP (dATP) is used, it acts as a myosin activator, enhancing cross-bridge binding and cycling. In vivo, we have demonstrated that elevated dATP levels increase basal cardiac function and rescues function of infarcted rodent and pig hearts. Here we investigate the molecular mechanism underlying this physiological effect...
April 2017: Protein Science: a Publication of the Protein Society
Gema Plumé Gimeno, Marco Bustamante-Balén, Carla Satorres Paniagua, Francia Carolina Díaz Jaime, Maria José Cejalvo Andújar
Due to the rising prevalence of coronary heart disease, endoscopists are more frequently performing a polypectomy in patients on antiplatelet therapy (APT) and dual antiplatelet therapy (DATP). Despite the availability of several guidelines with regard to the management of antiplatelet drugs during the periprocedure period, there is still variability in the current clinical practice. This may be influenced by the low quality of the evidence supporting recommendations, because most of the studies dealing with APT and polypectomy are observational and retrospective, and include mainly small (< 10 mm) polyps...
January 2017: Revista Española de Enfermedades Digestivas
Sam L Teichman, Kassandra S Thomson, Michael Regnier
Chronic inotropic therapy is effective for the treatment of heart failure with reduced ejection fraction, but has been limited by adverse long-term safety profiles, development of tolerance, and the need for chronic parenteral administration. A safe and convenient therapeutic agent that produces sustained inotropic effects could improve symptoms, functional capacity, and quality of life. Small amounts of 2-deoxy-adenosine triphosphate (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle...
2017: Handbook of Experimental Pharmacology
Stephen C Kolwicz, Guy L Odom, Sarah G Nowakowski, Farid Moussavi-Harami, Xiaolan Chen, Hans Reinecke, Stephen D Hauschka, Charles E Murry, Gregory G Mahairas, Michael Regnier
Impaired systolic function, resulting from acute injury or congenital defects, leads to cardiac complications and heart failure. Current therapies slow disease progression but do not rescue cardiac function. We previously reported that elevating the cellular 2 deoxy-ATP (dATP) pool in transgenic mice via increased expression of ribonucleotide reductase (RNR), the enzyme that catalyzes deoxy-nucleotide production, increases myosin-actin interaction and enhances cardiac muscle contractility. For the current studies, we initially injected wild-type mice retro-orbitally with a mixture of adeno-associated virus serotype-6 (rAAV6) containing a miniaturized cardiac-specific regulatory cassette (cTnT(455)) composed of enhancer and promotor portions of the human cardiac troponin T gene (TNNT2) ligated to rat cDNAs encoding either the Rrm1 or Rrm2 subunit...
February 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Seungjun Song, Hyang-Hee Seo, Se-Yeon Lee, Chang Yeon Lee, Jiyun Lee, Kyung-Jong Yoo, Cheesoon Yoon, Eunhyun Choi, Ki-Chul Hwang, Seahyoung Lee
Heart diseases such as myocardial infarction (MI) can damage individual cardiomyocytes, leading to the activation of cell death programs. The most scrutinized type of cell death in the heart is apoptosis, and one of the key events during the propagation of apoptotic signaling is the formation of apoptosomes, which relay apoptotic signals by activating caspase-9. As one of the major components of apoptosomes, apoptotic protease activating factor 1 (Apaf-1) facilitates the formation of apoptosomes containing cytochrome c (Cyto-c) and deoxyadenosine triphosphate (dATP)...
September 18, 2015: Biochemical and Biophysical Research Communications
Shin Kadota, John Carey, Hans Reinecke, James Leggett, Sam Teichman, Michael A Laflamme, Charles E Murry, Michael Regnier, Gregory G Mahairas
AIMS: Heart failure remains a leading cause of morbidity, hospitalizations, and deaths. We previously showed that overexpression of the enzyme ribonucleotide reductase (RNR) in cardiomyocytes increased levels of the myosin activator, 2-deoxy-ATP, catalysed enhanced contraction, and improved cardiac performance in rodent hearts. Here we used a swine model of myocardial infarction (MI) to test preliminarily a novel gene therapy for heart failure based on delivery of the human RNR enzyme complex under the control of a cardiac-specific promoter via an adeno-associated virus serotype 6 vector--designated as BB-R12...
August 2015: European Journal of Heart Failure
Farid Moussavi-Harami, Maria V Razumova, Alice W Racca, Yuanhua Cheng, April Stempien-Otero, Michael Regnier
We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure...
February 2015: Journal of Molecular and Cellular Cardiology
Scott D Lundy, Sean A Murphy, Sarah K Dupras, Jin Dai, Charles E Murry, Michael A Laflamme, Michael Regnier
The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is a promising strategy to treat myocardial infarction and reverse heart failure, but to date the contractile benefit in most studies remains modest. We have previously shown that the nucleotide 2-deoxyadenosine triphosphate (dATP) can substitute for ATP as the energy substrate for cardiac myosin, and increasing cellular dATP content by globally overexpressing ribonucleotide reductase (R1R2) can dramatically enhance cardiac contractility...
July 2014: Journal of Molecular and Cellular Cardiology
Sarah G Nowakowski, Stephen C Kolwicz, Frederick Steven Korte, Zhaoxiong Luo, Jacqueline N Robinson-Hamm, Jennifer L Page, Frank Brozovich, Robert S Weiss, Rong Tian, Charles E Murry, Michael Regnier
We previously demonstrated that cardiac myosin can use 2-deoxy-ATP (dATP) as an energy substrate, that it enhances contraction and relaxation with minimal effect on calcium-handling properties in vitro, and that contractile enhancement occurs with only minor elevation of cellular [dATP]. Here, we report the effect of chronically enhanced dATP concentration on cardiac function using a transgenic mouse that overexpresses the enzyme ribonucleotide reductase (TgRR), which catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis...
April 9, 2013: Proceedings of the National Academy of Sciences of the United States of America
Karol Bialkowski, Anna Szpila, Kazimierz S Kasprzak
Abstract Mammalian MTH1 protein is an antimutagenic (2'-deoxy)ribonucleoside 5'-triphosphate pyrophosphohydrolase that prevents the incorporation of oxidatively modified nucleotides into nucleic acids. It decomposes most specifically the miscoding products of oxidative damage to purine nucleic acid precursors (e.g. 8-oxo-dGTP, 2-oxo-dATP, 2-oxo-ATP, 8-oxo-GTP) that may cause point mutations or transcription errors when incorporated into DNA and RNA, respectively. The increased expression of MTH1 mRNA and MTH1 protein was previously proposed as a molecular marker of oxidative stress...
August 2009: Radiation Research
Hyun-Eui Kim, Fenghe Du, Min Fang, Xiaodong Wang
Apoptosis in metazoans is executed by a group of intracellular proteases named caspases. One of the caspase-activating pathways in mammals is initiated by the release of cytochrome c from mitochondria to cytosol, where it binds to Apaf-1 to form a procaspase-9-activating heptameric protein complex named apoptosome. We report here the reconstitution of this pathway with purified recombinant Apaf-1, procaspase-9, procaspase-3, and cytochrome c from horse heart. Apaf-1 contains a dATP as a cofactor. Cytochrome c binding to Apaf-1 induces hydrolysis of dATP to dADP, which is subsequently replaced by exogenous dATP...
December 6, 2005: Proceedings of the National Academy of Sciences of the United States of America
Federica Sinibaldi, Giampiero Mei, Fabio Polticelli, M Cristina Piro, Barry D Howes, Giulietta Smulevich, Roberto Santucci, Franca Ascoli, Laura Fiorucci
An increasing body of evidence ascribes to misfolded forms of cytochrome c (cyt c) a role in pathophysiological events such as apoptosis and disease. Here, we examine the conformational changes induced by lipid binding to horse heart cyt c at pH 7 and study the ability of ATP (and other nucleotides) to refold several forms of unfolded cyt c such as oleic acid-bound cyt c, nicked cyt c, and acid denatured cyt c. The CD and fluorescence spectra demonstrate that cyt c unfolded by oleic acid has an intact secondary structure, and a disrupted tertiary structure and heme environment...
April 2005: Protein Science: a Publication of the Protein Society
Bishow B Adhikari, Michael Regnier, Anthony J Rivera, Kareen L Kreutziger, Donald A Martyn
We examined the influence of cross-bridge cycling kinetics on the length dependence of steady-state force and the rate of force redevelopment (k(tr)) during Ca(2+)-activation at sarcomere lengths (SL) of 2.0 and 2.3 microm in skinned rat cardiac trabeculae. Cross-bridge kinetics were altered by either replacing ATP with 2-deoxy-ATP (dATP) or by reducing [ATP]. At each SL dATP increased maximal force (F(max)) and Ca(2+)-sensitivity of force (pCa(50)) and reduced the cooperativity (n(H)) of force-pCa relations, whereas reducing [ATP] to 0...
September 2004: Biophysical Journal
Gang-Hua Lang, Yong Wang, Nakao Nomura, Masatoshi Matsumura
Telomerase is a ribonucleoprotein enzyme that can elongate telomeric DNA, which is thought to be required for the development of cellular immortality and oncogenesis in mammals. We examined telomerase activity in tissues and primary cultured lymphoid cells of adult penaeid shrimps. Using the telomeric repeat amplification protocol (TRAP), we studied the characteristics of a putative novel telomerase in Penaeus japonicus. This telomerase could be inactivated by heating or treatment with RNase A or proteinase K...
July 2004: Marine Biotechnology
Z Chen, Y R Xin, Y Jiang, J X Jiang
AIM: To clone a novel mouse GABAA-receptor-associated protein like 2 (Gabarapl2) gene, and to analysis its primary function. METHODS: With the aid of computer, the human GABARAPL2 cDNA was used as information probe to search mouse EST database of GenBank for mouse homolog. A series of overlapping EST were found and assembled into an EST contig using Genetics Computer Group (GCG) ASSEMBLY program. The existence of the gene was then identified by experiment. Northern blotting was performed to hybridize [alpha-32P]dATP labeled probe with mRNA of 11 different mouse tissues that had been transferred to the nylon membrane...
August 2001: Acta Pharmacologica Sinica
V I Kazakov, V M Mikhaĭlov
The study deals with apoptosis of cardiomyocytes of adult mdx mice. Our previous investigation of the total DNA from mdx mice myocardium in 0.5% agarose and 5% PAAG revealed middle sized DNA fragments about 64 kb only. The DNA electrophoresis in 5% PAAG after alpha-32P-dATP incorporation into DNA, fragments mediated by terminal transferase, showed no presence of smaller DNA fragments. The low size DNA fragments (0.2, 0.4 and 11.0 kb) were observed only following stress (a 5 min swimming in water bath) by means of alpha-32P-dATP incorporation mediated by TdT reaction...
2001: Tsitologiia
M Kruidering, G I Evan
Caspase-8 is a member of the cysteine proteases, which are implicated in apoptosis and cytokine processing. Like all caspases, caspase-8 is synthesized as an inactive single polypeptide chain zymogen procaspase and is activated by proteolytic cleavage, through either autoactivation after recruitment into a multimeric complex or trans-cleavage by other caspases. Thus, ligand binding-induced trimerization of death receptors results in recruitment of the receptor-specific adapter protein Fas-associated death domain (FADD), which then recruits caspase-8...
August 2000: IUBMB Life
A M Chinnaiyan
Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise. Genetic analyses of the nematode C elegans identified three core components of the suicide apparatus which include CED-3, CED-4, and CED-9. An analogous set of core constituents exists in mammalian cells and includes caspase-9, Apaf-1, and bcl-2/xL, respectively. CED-3 and CED-4, along with their mammalian counterparts, function to kill cells, whereas CED-9 and its mammalian equivalents protect cells from death...
April 1999: Neoplasia: An International Journal for Oncology Research
M Regnier, A J Rivera, Y Chen, P B Chase
To investigate the kinetic parameters of the crossbridge cycle that regulate force and shortening in cardiac muscle, we compared the mechanical properties of cardiac trabeculae with either ATP or 2-deoxy-ATP (dATP) as the substrate for contraction. Comparisons were made in trabeculae from untreated rats (predominantly V1 myosin) and those treated with propylthiouracil (PTU; V3 myosin). Steady-state hydrolytic activity of cardiac heavy meromyosin (HMM) showed that PTU treatment resulted in >40% reduction of ATPase activity...
June 23, 2000: Circulation Research
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