FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2004809359> ?p ?o ?g. }

• W2004809359 endingPage "713" @default.
• W2004809359 startingPage "701" @default.
• W2004809359 abstract "We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart. We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart. Large myocardial infarctions are an important cause of heart failure.1Pfefer M.A. Left ventricular remodeling after acute infarction.Annu Rev Med. 1995; 46: 455-456Crossref PubMed Scopus (196) Google Scholar, 2Reimer K.A. Vander Heide R.S. Richard V.J. Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models.Am J Cardiol. 1993; 72: 13G-21GAbstract Full Text PDF PubMed Scopus (118) Google Scholar The postinfarction heart gradually dilates to maintain cardiac output in a process called remodeling.1Pfefer M.A. Left ventricular remodeling after acute infarction.Annu Rev Med. 1995; 46: 455-456Crossref PubMed Scopus (196) Google Scholar However, excessive remodeling late in the chronic stage leads to a loss of cardiac performance and heart failure.1Pfefer M.A. Left ventricular remodeling after acute infarction.Annu Rev Med. 1995; 46: 455-456Crossref PubMed Scopus (196) Google Scholar The process of remodeling is complex and involves a variety of factors, including myocyte hypertrophy, inflammation, oxidative stress, fibrosis, late cell death, angiogenesis, and the dynamics of the infarct scar.3Shan K. Kurrelmeyer K. Seta Y. Wang F. Dibbs Z. Deswal A. Lee-Jackson D. Mann D.L. The role of cytokines in disease progression in heart failure.Curr Opin Cardiol. 1997; 12: 218-223Crossref PubMed Scopus (94) Google Scholar, 4Weisman H.F. Bush D.E. Mannisi J.A. Weisfeldt M.L. Healy B. Cellular mechanisms of myocardial infarct expansion.Circulation. 1988; 78: 186-201Crossref PubMed Scopus (297) Google Scholar Autophagy is a physiological self-degradation process that proceeds via the lysosomal digestive pathway and functions to maintain the intracellular environment. Autophagic activation occurs in the normal heart under stable conditions, as well as in several heart diseases, including heart failure, hypertrophy, ischemic cardiomyopathy, and cardiac senescence.5Knaapen M.W. Davies M.J. De Bie M. Haven A.J. Martinet W. Kockx M.M. Apoptotic versus autophagic cell death in heart failure.Cardiovasc Res. 2001; 51: 304-312Crossref PubMed Scopus (219) Google Scholar, 6Shimomura H. Terasaki F. Hayashi T. Kitaura Y. Isomura T. Suma H. Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy.Jpn Circ J. 2001; 65: 965-968Crossref PubMed Scopus (154) Google Scholar, 7Takemura G. Miyata S. Kawase Y. Okada H. Maruyama R. Fujiwara H. Autophagic degeneration and death of cardiomyocytes in heart failure.Autophagy. 2006; 2: 212-214Crossref PubMed Scopus (90) Google Scholar, 8Hein S. Arnon E. Kostin S. Schönburg M. Elsässer A. Polyakova V. Bauer E.P. Klövekorn W.P. Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms.Circulation. 2003; 107: 984-991Crossref PubMed Scopus (831) Google Scholar, 9Nakai A. Yamaguchi O. Takeda T. Higuchi Y. Hikoso S. Taniike M. Omiya S. Mizote I. Matsumura Y. Asahi M. Nishida K. Hori M. Mizushima N. Otsu K. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress.Nat Med. 2007; 13: 619-624Crossref PubMed Scopus (1191) Google Scholar, 10Yan L. Vatner D.E. Kim S.J. Ge H. Masurekar M. Massover W.H. Yang G. Matsui Y. Sadoshima J. Vatner S.F. Autophagy in chronically ischemic myocardium.Proc Natl Acad Sci U S A. 2005; 102: 13807-13812Crossref PubMed Scopus (443) Google Scholar, 11Shinmura K. Tamaki K. Sano M. Murata M. Yamakawa H. Ishida H. Fukuda K. Impact of long-term caloric restriction on cardiac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associated with aging.J Mol Cell Cardiol. 2011; 50: 117-127Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar We previously reported that autophagy is activated following myocardial infarction and that it compensates for the lack of energy in affected cardiomyocytes through digestion and recycling of the constituents of the cells.12Kanamori H. Takemura G. Goto K. Maruyama R. Tsujimoto A. Ogino A. Takeyama T. Kawaguchi T. Watanabe T. Fujiwara T. Fujiwara H. Seishima M. Minatoguchi S. The role of autophagy emerging in post infarction cardiac remodeling.Cardiovasc Res. 2011; 91: 330-339Crossref PubMed Scopus (158) Google Scholar In that study, augmenting autophagy mitigated adverse postinfarction cardiac remodeling and preserved cardiac performance, whereas inhibition of autophagy had the opposite effect.12Kanamori H. Takemura G. Goto K. Maruyama R. Tsujimoto A. Ogino A. Takeyama T. Kawaguchi T. Watanabe T. Fujiwara T. Fujiwara H. Seishima M. Minatoguchi S. The role of autophagy emerging in post infarction cardiac remodeling.Cardiovasc Res. 2011; 91: 330-339Crossref PubMed Scopus (158) Google Scholar These findings suggest that enhancing autophagic activity could be a useful therapeutic strategy against the progression of postinfarction remodeling. Resveratrol is a natural polyphenol present in many plant-based foods, including peanuts, cranberries, blueberries, and grapes. It is well known for its potential health benefits related to its reported anti-inflammatory, antioxidative, antiaging, cardioprotective, neuroprotective, and antitumorigenic properties.13Baur J.A. Sinclair D.A. Therapeutic potential of resveratrol: the in vivo evidence.Nat Rev Drug Discov. 2006; 5: 493-506Crossref PubMed Scopus (3114) Google Scholar Early pharmacological studies showed that at therapeutic doses, this compound is nontoxic, easily absorbed, and well tolerated by humans.14Brisdelli F. D’Andrea G. Bozzi A. Resveratrol: a natural polyphenol with multiple chemopreventive properties.Curr Drug Metab. 2009; 10: 530-546Crossref PubMed Scopus (137) Google Scholar Importantly, resveratrol was recently reported to strongly accelerate autophagy in vivo.15Morselli E. Mariño G. Bennetzen M.V. Eisenberg T. Megalou E. Schroeder S. Cabrera S. Bénit P. Rustin P. Criollo A. Kepp O. Galluzzi L. Shen S. Malik S.A. Maiuri M.C. Horio Y. López-Otín C. Andersen J.S. Tavernarakis N. Madeo F. Kroemer G. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.J Cell Biol. 2011; 192: 615-629Crossref PubMed Scopus (352) Google Scholar The signaling molecules stimulated by resveratrol in the cardiovascular system include AMP-activated protein kinase (AMPK), Akt, endothelial nitric oxide synthase (eNOS), manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), silent information regulator-1 (Sirt1), IL-6, NF-κB, tumor necrosis factor-α (TNF-α), and adiponectin.16Dolinsky V.W. Dyck J.R. Calorie restriction and resveratrol in cardiovascular health and disease.Biochim Biophys Acta. 2011; 1812: 1477-1489Crossref PubMed Scopus (128) Google Scholar However, the network formed by these molecules is complex, and the key autophagic factors associated with resveratrol have not yet been identified. There have been a number of reports that resveratrol exerts various cardioprotective effects, including mitigation of left ventricular (LV) hypertrophy, reduction of myocardial infarct size, attenuation of ischemia-reperfusion injury, improvement of vascular function, and improvement of cardiac function in cardiomyopathy.16Dolinsky V.W. Dyck J.R. Calorie restriction and resveratrol in cardiovascular health and disease.Biochim Biophys Acta. 2011; 1812: 1477-1489Crossref PubMed Scopus (128) Google Scholar On the other hand, there have been no reports on the effect of resveratrol on postinfarction cardiac remodeling and the role of autophagy. Our aim in the present study was to investigate the possible beneficial effect of resveratrol on postinfarction LV remodeling and to clarify the related molecular mechanisms. We addressed this issue by examining the effects of resveratrol in an established murine model of heart failure caused by an old myocardial infarction. This study conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996) and was approved by the institutional animal research committee of Gifu University. Myocardial infarction was generated in male C57BL/6J mice (8 to 10 weeks of age; CLEA Japan, Tokyo, Japan) by ligating the left coronary artery as previously described.12Kanamori H. Takemura G. Goto K. Maruyama R. Tsujimoto A. Ogino A. Takeyama T. Kawaguchi T. Watanabe T. Fujiwara T. Fujiwara H. Seishima M. Minatoguchi S. The role of autophagy emerging in post infarction cardiac remodeling.Cardiovasc Res. 2011; 91: 330-339Crossref PubMed Scopus (158) Google Scholar Sham-treated animals underwent the same surgical procedure without left coronary artery ligation. We induced myocardial infarction in 107 mice, of which 80 survived 4 weeks after the procedure (survival rate: 75%). Each of the surviving mice was assigned to one of the following five treatment groups after echocardiographic examination: vehicle (control, n = 16); 5 mg/kg per day, or low-dose, resveratrol (Sigma-Aldrich, St. Louis, MO; n = 16); 50 mg/kg per day, or high-dose, resveratrol (n = 16); 10 mg/kg per day chloroquine (Sigma-Aldrich; n = 16); and high-dose resveratrol plus chloroquine (n = 16). The agents were administered for 14 days using subcutaneously embedded osmotic minipumps (ALZET; DURECT, Cupertino, CA). We used two doses of resveratrol (5 mg/kg and 50 mg/kg) to assess the dose-dependent effects. Both doses were previously reported not to cause apparent adverse effects in the rodent heart.16Dolinsky V.W. Dyck J.R. Calorie restriction and resveratrol in cardiovascular health and disease.Biochim Biophys Acta. 2011; 1812: 1477-1489Crossref PubMed Scopus (128) Google Scholar Chloroquine is a membrane-permeant lysosomal inhibitor that acts by inhibiting vacuolar H+-ATPase. It also inhibits autophagosome–lysosome fusion, thereby preventing the final digestion step in autophagy. Chloroquine is frequently used to experimentally inhibit autophagy,17Iwai-Kanai E. Yuan H. Huang C. Sayen M.R. Perry-Garza C.N. Kim L. Gottlieb R.A. A method to measure cardiac autophagic flux in vivo.Autophagy. 2008; 4: 322-329Crossref PubMed Scopus (220) Google Scholar and the dose of chloroquine used here was previously reported to inhibit autophagy in mice, without apparent side effects.11Shinmura K. Tamaki K. Sano M. Murata M. Yamakawa H. Ishida H. Fukuda K. Impact of long-term caloric restriction on cardiac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associated with aging.J Mol Cell Cardiol. 2011; 50: 117-127Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar To assess the effects of these treatments on mice without infarction, sham-operated mice were assigned to the same groups 4 weeks after surgery (n = 8 each). All mice were examined 2 weeks after starting treatment (6 weeks after surgery). Echocardiography and cardiac catheterization were performed before sacrifice as described previously.12Kanamori H. Takemura G. Goto K. Maruyama R. Tsujimoto A. Ogino A. Takeyama T. Kawaguchi T. Watanabe T. Fujiwara T. Fujiwara H. Seishima M. Minatoguchi S. The role of autophagy emerging in post infarction cardiac remodeling.Cardiovasc Res. 2011; 91: 330-339Crossref PubMed Scopus (158) Google Scholar, 18Kanamori H. Takemura G. Maruyama R. Goto K. Tsujimoto A. Ogino A. Li L. Kawamura I. Takeyama T. Kawaguchi T. Nagashima K. Fujiwara T. Fujiwara H. Seishima M. Minatiguchi S. Functional significance and morphological characterization of starvation-induced autophagy in the adult heart.Am J Pathol. 2009; 174: 1705-1714Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Once the physiological measurements were complete, mice were sacrificed, and the hearts were removed, weighed, and cut into halves transversely between the atrioventricular groove and the apex. The basal specimens were fixed in 10% buffered formalin, embedded in paraffin, cut into sections (4-μm thick), and then stained with H&E or Masson’s trichrome. Cardiomyocyte size (measured as the transverse diameter of myocytes cut at the level of the nucleus) was assessed in randomly chosen high-power fields (600×) in each section. After deparaffinization, the sections (4-μm thick) were incubated with a primary antibody against microtubule-associated protein-1 light chain 3 (LC3; MBL International, Woburn, MA) or atrial natriuretic peptide (ANP; Santa Cruz Biotechnology, Santa Cruz, CA). To observe autophagic activity in cardiomyocytes, sections immunostained with anti-LC3 followed by Alexa 488 (green; Molecular Probes, Sunnyvale, CA) were also labeled with anti-myoglobin antibody (DAKO Japan, Kyoto, Japan) followed by Alexa 568 (red; Molecular Probes). These sections were then counterstained with Hoechst 33342 and observed under a confocal microscope (LSM510; Carl Zeiss, Oberkochen, Germany). A Vectastain Elite ABC system (Vector Laboratories, Burlingame, CA) was used for immunostaining of ANP; diaminobenzidine served as the chromogen, and the nuclei were counterstained with hematoxylin. For in situ terminal dUTP nick end-labeling (TUNEL), tissue sections were first stained with Fluorescein-FragEL (Oncogene Research Products, Boston, MA) and then labeled with anti-myoglobin antibody followed by Alexa 568. Quantitative assessments, including numbers of immunopositive dots within cells, were performed in 20 randomly chosen high-power fields (600×) using a multipurpose color image processor (Nireco, Kyoto, Japan). Border areas were defined as areas containing both infarcted and salvaged myocardium within a high-power field, whereas remote areas were myocardial regions far remote from any infarction. Cardiac tissue was quickly cut into 1-mm cubes, immersion fixed in 2.5% glutaraldehyde in 0.1 mol/L phosphate buffer (pH 7.4) overnight at 4°C, and postfixed in 1% buffered osmium tetroxide. The specimens were then dehydrated through a graded ethanol series and embedded in epoxy resin. Ultrathin sections (90 nm), double-stained with uranyl acetate and lead citrate, were examined in an electron microscope (H-800; Hitachi, Tokyo, Japan). Proteins (50 μg) extracted from hearts were subjected to 10% or 15% polyacrylamide gel electrophoresis and then transferred onto polyvinylidene difluoride membranes. The membranes were then probed using primary antibodies against LC3 (MBL International), p62 (MBL International), ANP (Santa Cruz Biotechnology), Sirt1 (Millipore, Billerica, MA), and AMPK, phosphorylated AMPK (p-AMPK), p70 S6 kinase (p70S6K), phosphorylated p70 S6 kinase (p-p70S6K), mTOR, phosphorylated mTOR (p-mTOR), Akt, phosphorylated Akt (p-Akt; all from Cell Signaling Technology, Danvers, MA), histone H3, acetylated-histone H3 (both from Calbiochem, Darmstadt, Germany), and manganese-superoxide dismutase (MnSOD; Millipore), after which the blots were visualized using enhanced chemiluminescence (Amersham/GE Healthcare, Little Chalfont, United Kingdom). α-Tubulin (analyzed using an antibody from Santa Cruz Biotechnology) served as the loading control. The ATP content in the heart was measured using an ATP bioluminescent assay kit (TOYO Ink, Tokyo, Japan). Cardiomyocytes were isolated from 1-day-old neonatal C57BL6 mice by the previously reported method.19Wang L. Feng Z.P. Kondo C.S. Sheldon R.S. Duff H.J. Developmental changes in the delayed rectifier K+ channels in mouse heart.Circ Res. 1996; 79: 79-85Crossref PubMed Scopus (200) Google Scholar The cardiomyocytes were plated on laminin-coated culture dishes or slide glass chambers and incubated in Dulbecco’s modified Eagle’s medium (Sigma-Aldrich) containing 5% fetal bovine serum (HyClone; Thermo Scientific, Waltham, MA) at 37°C. Two days after plating, the cells were treated with saline, 100 μmol/L resveratrol, or 3 μmol/L chloroquine,17Iwai-Kanai E. Yuan H. Huang C. Sayen M.R. Perry-Garza C.N. Kim L. Gottlieb R.A. A method to measure cardiac autophagic flux in vivo.Autophagy. 2008; 4: 322-329Crossref PubMed Scopus (220) Google Scholar with or without simultaneous treatment with 20 μmol/L AMPK inhibitor compound C (Calbiochem).20Lee M. Hwang J.T. Lee H.J. Jung S.N. Kang I. Chi S.G. Kim S.S. Ha J. AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells.J Biol Chem. 2003; 278 (3965–3961)Google Scholar Four hours later, the cells were used for Western blot analysis for AMPK and p-AMPK, immunofluorescence for LC3 using anti-LC3 antibody as the primary antibody and Alexa 488 as the secondary antibody, electron microscopy, and ATP measurement (Sigma-Aldrich). Data are expressed as means ± SEM. The significance of differences between groups was evaluated using one-way analysis of variance with a post hoc Newman-Keuls multiple comparisons test or a repeated measures analysis of variance (Table 1). Values of P < 0.05 were considered significant.Table 1Cardiac Function during Physiological Examinations Carried Out Before and After Treatment (4 and 6 Weeks after Surgery, Respectively)ShamMyocardial infarctionVehicle n = 8Vehicle n = 16RSV 5 mg n = 16RSV 50 mg n = 16Chloroquine n = 16RSV + Cq n = 16Before treatment LVEDd, mm3.21 ± 0.044.77 ± 0.08∗P < 0.05 versus the vehicle-treated sham group.4.77 ± 0.08∗P < 0.05 versus the vehicle-treated sham group.4.68 ± 0.06∗P < 0.05 versus the vehicle-treated sham group.4.742 ± 0.03∗P < 0.05 versus the vehicle-treated sham group.4.69 ± 0.05∗P < 0.05 versus the vehicle-treated sham group. LVEF, %73.9 ± 1.338.8 ± 1.3∗P < 0.05 versus the vehicle-treated sham group.36.4 ± 1.5∗P < 0.05 versus the vehicle-treated sham group.38.5 ± 0.8∗P < 0.05 versus the vehicle-treated sham group.38.5 ± 1.0∗P < 0.05 versus the vehicle-treated sham group.38.6 ± 0.43∗P < 0.05 versus the vehicle-treated sham group. Heart rate, b.p.m.499 ± 9491 ± 10489 ± 11488 ± 7488 ± 4486 ± 5After treatment LVEDd, mm3.17 ± 0.054.93 ± 0.09∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.4.98 ± 0.06∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.4.14 ± 0.04∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.5.20 ± 0.06∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.4.92 ± 0.04∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value. LVEF, %73.2 ± 0.7835.7 ± 1.2∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.34.8 ± 1.1∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.46.9 ± 0.86∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.32.0 ± 1.4∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.35.7 ± 0.58∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value. Heart rate, b.p.m.497 ± 17490 ± 7484 ± 8487 ± 7494 ± 7493 ± 6 SBP, mm Hg116.0 ± 1.688.0 ± 1.5∗P < 0.05 versus the vehicle-treated sham group.91.5 ± 0.7∗P < 0.05 versus the vehicle-treated sham group.95.2 ± 0.9∗P < 0.05 versus the vehicle-treated sham group.‡P < 0.05 versus the vehicle-treated infarction group.89.6 ± 1.7∗P < 0.05 versus the vehicle-treated sham group.‡P < 0.05 versus the vehicle-treated infarction group.90.3 ± 1.4∗P < 0.05 versus the vehicle-treated sham group. LVEDP, mm Hg0.1 ± 0.15.0 ± 0.3∗P < 0.05 versus the vehicle-treated sham group.5.7 ± 0.7∗P < 0.05 versus the vehicle-treated sham group.1.6 ± 0.1∗P < 0.05 versus the vehicle-treated sham group.‡P < 0.05 versus the vehicle-treated infarction group.7.9 ± 0.6∗P < 0.05 versus the vehicle-treated sham group.‡P < 0.05 versus the vehicle-treated infarction group.5.5 ± 0.4∗P < 0.05 versus the vehicle-treated sham group. +dP/dt, mm Hg/s10,246 ± 1134435 ± 79∗P < 0.05 versus the vehicle-treated sham group.4661 ± 153∗P < 0.05 versus the vehicle-treated sham group.6675 ± 251∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.3627 ± 105∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the corresponding pre-treatment value.4540 ± 121∗P < 0.05 versus the vehicle-treated sham group. −dP/dt, mm Hg/s−9017 ± 359−3743 ± 137∗P < 0.05 versus the vehicle-treated sham group.−3548 ± 158∗P < 0.05 versus the vehicle-treated sham group.−5005 ± 282∗P < 0.05 versus the vehicle-treated sham group.‡P < 0.05 versus the vehicle-treated infarction group.−3324 ± 117∗P < 0.05 versus the vehicle-treated sham group.‡P < 0.05 versus the vehicle-treated infarction group.−4112 ± 127∗P < 0.05 versus the vehicle-treated sham group.b.p.m., beats per minute; Cq, chloroquine; LVEDd, left ventricular end-diastolic diameter; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; RSV, resveratrol; SBP, systolic blood pressure.∗ P < 0.05 versus the vehicle-treated sham group.† P < 0.05 versus the corresponding pre-treatment value.‡ P < 0.05 versus the vehicle-treated infarction group. Open table in a new tab b.p.m., beats per minute; Cq, chloroquine; LVEDd, left ventricular end-diastolic diameter; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; RSV, resveratrol; SBP, systolic blood pressure. All of the mice in each group survived through the 2 weeks of treatment (6 weeks after surgery). However, echocardiography and cardiac catheterization revealed that in the vehicle-treated group, there was a progressive worsening of LV remodeling during this period, with enlargement of the LV cavity and diminishing cardiac performance, ie, reduced LV ejection fraction, reduced maximal and minimal change in pressure over time (±LV dP/dt), reduced LV systolic pressure, and increased LV end-diastolic pressure (Table 1 and Figure 1A). By contrast, the LV dilation and dysfunction were attenuated in the high-dose (but not the low-dose) resveratrol group; LV systolic pressure was preserved, and LV end-diastolic pressure was significantly lower than in the other treatment groups. Treatment with chloroquine had the opposite effect; it increased LV end-diastolic pressure, dilated the LV cavity, and exacerbated the reduction in cardiac performance. Moreover, the group treated with a combination of high-dose resveratrol plus chloroquine showed cardiac remodeling and dysfunction similar to that in the vehicle group. In other words, chloroquine appeared to block the beneficial effects of high-dose resveratrol. Neither high-dose resveratrol nor chloroquine affected left ventricular geometry or cardiac function in the sham-operated heart (data not shown). Treatment with high-dose resveratrol also significantly suppressed elongation of the infarct wall segment and reduced heart-to-body weight ratios, lung-to-body weight ratios, and cardiomyocyte size (Figure 1B and Table 2). Thus, high-dose resveratrol attenuated cardiac hypertrophy, adverse remodeling, and pulmonary congestion. Conversely, treatment with chloroquine exacerbated LV dilation and the accompanying elongation of the infarct wall segment (Figure 1B and Table 2).Table 2Cardiac Morphometry and PathologyShamMyocardial infarctionVehicle n = 8Vehicle n = 16RSV 5 mg n = 16RSV 50 mg n = 16Chloroquine n = 16RSV + Cq n = 16Body weight (g)30.2 ± 0.4626.7 ± 0.44∗P < 0.05 versus the vehicle-treated sham group.26.9 ± 0.42∗P < 0.05 versus the vehicle-treated sham group.27.1 ± 0.35∗P < 0.05 versus the vehicle-treated sham group.26.3 ± 0.40∗P < 0.05 versus the vehicle-treated sham group.27.1 ± 0.41∗P < 0.05 versus the vehicle-treated sham group.Heart weight (g)0.12 ± 0.0040.14 ± 0.007∗P < 0.05 versus the vehicle-treated sham group.0.13 ± 0.004∗P < 0.05 versus the vehicle-treated sham group.0.12 ± 0.004†P < 0.05 versus the vehicle-treated infarction group.0.13 ± 0.006∗P < 0.05 versus the vehicle-treated sham group.0.13 ± 0.005∗P < 0.05 versus the vehicle-treated sham group.Heart/body ratio (mg/g)3.83 ± 0.105.18 ± 0.21∗P < 0.05 versus the vehicle-treated sham group.4.78 ± 0.15∗P < 0.05 versus the vehicle-treated sham group.4.24 ± 0.12∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the vehicle-treated infarction group.4.96 ± 0.17∗P < 0.05 versus the vehicle-treated sham group.4.72 ± 0.17∗P < 0.05 versus the vehicle-treated sham group.Lung/Body ratio (mg/g)4.92 ± 0.105.49 ± 0.13∗P < 0.05 versus the vehicle-treated sham group.5.56 ± 0.12∗P < 0.05 versus the vehicle-treated sham group.4.83 ± 0.12†P < 0.05 versus the vehicle-treated infarction group.5.67 ± 0.19∗P < 0.05 versus the vehicle-treated sham group.5.55 ± 0.35∗P < 0.05 versus the vehicle-treated sham group.%Infarct segment49.9 ± 1.4950.9 ± 1.5340.6 ± 2.06†P < 0.05 versus the vehicle-treated infarction group.56.4 ± 1.68†P < 0.05 versus the vehicle-treated infarction group.47.2 ± 1.55Infarct length (mm)16.0 ± 0.4715.5 ± 0.3914.4 ± 0.25†P < 0.05 versus the vehicle-treated infarction group.16.7 ± 0.44†P < 0.05 versus the vehicle-treated infarction group.15.1 ± 0.58Infarct thickness (mm)2.4 ± 0.062.4 ± 0.082.4 ± 0.062.4 ± 0.032.4 ± 0.09Myocyte size (μm)12.7 ± 0.316.5 ± 0.3∗P < 0.05 versus the vehicle-treated sham group.16.4 ± 0.2∗P < 0.05 versus the vehicle-treated sham group.13.5 ± 0.1∗P < 0.05 versus the vehicle-treated sham group.†P < 0.05 versus the vehicle-treated infarction group.16.5 ± 0.2∗P < 0.05 versus the vehicle-treated sham group.16.5 ± 0.12∗P < 0.05 versus the vehicle-treated sham group.Cq, chloroquine; RSV, resveratrol.∗ P < 0.05 versus the vehicle-treated sham group.† P < 0.05 versus the vehicle-treated infarction group. Open table in a new tab Cq, chloroquine; RSV, resveratrol. Our physiological and morphological studies revealed that only the high-dose, not low-dose, resveratrol was effective, suggesting a dose-dependent effect of this compound. Thus, we performed the subsequent mechanistic studies (ie, biochemical analyses) using only the group treated with the high-dose, rather than the low-dose, resveratrol. We evaluated myocardial ANP expression as an index of heart failure severity. Western blot and immunohistochemical analyses showed that ANP expression in ventricular cardiomyocytes neighboring the infarct area was suppress" @default.
• W2004809359 created "2016-06-24" @default.
• W2004809359 creator A5010904129 @default.
• W2004809359 creator A5015604127 @default.
• W2004809359 creator A5022669876 @default.
• W2004809359 creator A5039503254 @default.
• W2004809359 creator A5039533635 @default.
• W2004809359 creator A5042104765 @default.
• W2004809359 creator A5046826386 @default.
• W2004809359 creator A5059646387 @default.
• W2004809359 creator A5061394480 @default.
• W2004809359 creator A5066511998 @default.
• W2004809359 creator A5067435988 @default.
• W2004809359 creator A5077773904 @default.
• W2004809359 creator A5082969604 @default.
• W2004809359 creator A5087541787 @default.
• W2004809359 creator A5089279058 @default.
• W2004809359 date "2013-03-01" @default.
• W2004809359 modified "2023-10-16" @default.
• W2004809359 title "Resveratrol Reverses Remodeling in Hearts with Large, Old Myocardial Infarctions through Enhanced Autophagy-Activating AMP Kinase Pathway" @default.
• W2004809359 cites W1968192793 @default.
• W2004809359 cites W1972687776 @default.
• W2004809359 cites W1977767269 @default.
• W2004809359 cites W1979141235 @default.
• W2004809359 cites W1980356545 @default.
• W2004809359 cites W2000870731 @default.
• W2004809359 cites W2001568034 @default.
• W2004809359 cites W2007846859 @default.
• W2004809359 cites W2009483242 @default.
• W2004809359 cites W2010523651 @default.
• W2004809359 cites W2011239505 @default.
• W2004809359 cites W2012040176 @default.
• W2004809359 cites W2019782533 @default.
• W2004809359 cites W2020036405 @default.
• W2004809359 cites W2027082110 @default.
• W2004809359 cites W2028317232 @default.
• W2004809359 cites W2036903182 @default.
• W2004809359 cites W2039635170 @default.
• W2004809359 cites W2044391218 @default.
• W2004809359 cites W2045697440 @default.
• W2004809359 cites W2047392757 @default.
• W2004809359 cites W2064729720 @default.
• W2004809359 cites W2068785830 @default.
• W2004809359 cites W2071228656 @default.
• W2004809359 cites W2077731318 @default.
• W2004809359 cites W2079848570 @default.
• W2004809359 cites W2087807630 @default.
• W2004809359 cites W2091412980 @default.
• W2004809359 cites W2094807579 @default.
• W2004809359 cites W2097164520 @default.
• W2004809359 cites W2119399459 @default.
• W2004809359 cites W2125121177 @default.
• W2004809359 cites W2125754274 @default.
• W2004809359 cites W2128694891 @default.
• W2004809359 cites W2132585963 @default.
• W2004809359 cites W2145771428 @default.
• W2004809359 cites W2152044516 @default.
• W2004809359 cites W2154587590 @default.
• W2004809359 cites W2156090275 @default.
• W2004809359 cites W2158827089 @default.
• W2004809359 cites W2158895600 @default.
• W2004809359 cites W2162777657 @default.
• W2004809359 cites W2162843846 @default.
• W2004809359 cites W2166978593 @default.
• W2004809359 cites W2167656141 @default.
• W2004809359 doi "https://doi.org/10.1016/j.ajpath.2012.11.009" @default.
• W2004809359 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23274061" @default.
• W2004809359 hasPublicationYear "2013" @default.
• W2004809359 type Work @default.
• W2004809359 sameAs 2004809359 @default.
• W2004809359 citedByCount "125" @default.
• W2004809359 countsByYear W20048093592013 @default.
• W2004809359 countsByYear W20048093592014 @default.
• W2004809359 countsByYear W20048093592015 @default.
• W2004809359 countsByYear W20048093592016 @default.
• W2004809359 countsByYear W20048093592017 @default.
• W2004809359 countsByYear W20048093592018 @default.
• W2004809359 countsByYear W20048093592019 @default.
• W2004809359 countsByYear W20048093592020 @default.
• W2004809359 countsByYear W20048093592021 @default.
• W2004809359 countsByYear W20048093592022 @default.
• W2004809359 countsByYear W20048093592023 @default.
• W2004809359 crossrefType "journal-article" @default.
• W2004809359 hasAuthorship W2004809359A5010904129 @default.
• W2004809359 hasAuthorship W2004809359A5015604127 @default.
• W2004809359 hasAuthorship W2004809359A5022669876 @default.
• W2004809359 hasAuthorship W2004809359A5039503254 @default.
• W2004809359 hasAuthorship W2004809359A5039533635 @default.
• W2004809359 hasAuthorship W2004809359A5042104765 @default.
• W2004809359 hasAuthorship W2004809359A5046826386 @default.
• W2004809359 hasAuthorship W2004809359A5059646387 @default.
• W2004809359 hasAuthorship W2004809359A5061394480 @default.
• W2004809359 hasAuthorship W2004809359A5066511998 @default.
• W2004809359 hasAuthorship W2004809359A5067435988 @default.
• W2004809359 hasAuthorship W2004809359A5077773904 @default.
• W2004809359 hasAuthorship W2004809359A5082969604 @default.
• W2004809359 hasAuthorship W2004809359A5087541787 @default.
• W2004809359 hasAuthorship W2004809359A5089279058 @default.

• next