title: Chronic heart damage following doxorubicin treatment is alleviated by lovastatin.
abstract: The anticancer efficacy of anthracyclines is limited by cumulative dose-dependent early and delayed cardiotoxicity resulting in congestive heart failure. Mechanisms responsible for anthracycline-induced heart damage are controversially discussed and effective preventive measures are preferable. Here, we analyzed the influence of the lipid lowering drug lovastatin on anthracycline-induced late cardiotoxicity three month after treatment of C57BL/6 mice with five low doses of doxorubicin (5×3mg/kg BW; i.p.). Doxorubicin increased the cardiac mRNA levels of BNP, IL-6 and CTGF, while the expression of ANP remained unchanged. Lovastatin counteracted these persisting cardiac stress responses evoked by the anthracycline. Doxorubicin-induced fibrotic alterations were neither detected by histochemical collagen staining of heart sections nor by analysis of the mRNA expression of collagens. Extensive qRT-PCR-array based analyses revealed a large increase in the mRNA level of heat shock protein Hspa1b in doxorubicin-treated mice, which was mitigated by lovastatin co-treatment. Electron microscopy together with qPCR-based analysis of mitochondrial DNA content indicate that lovastatin attenuates doxorubicin-stimulated hyperproliferation of mitochondria. This was not paralleled by increased expression of oxidative stress responsive genes or senescence-associated proteins. Echocardiographic analyses disclosed that lovastatin protects from the doxorubicin-induced decrease in the left ventricular posterior wall diameter (LVPWD), while constrictions in fractional shortening (FS) and ejection fraction (EF) evoked by doxorubicin were not amended by the statin. Taken together, the data suggest beneficial effects of lovastatin against doxorubicin-induced delayed cardiotoxicity. Clinical studies are preferable to scrutinize the usefulness of statins for the prevention of anthracycline-induced late cardiotoxicity.
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany. Electronic address: henninger@hhu.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Henninger
authors.affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Huelsenbeck
authors.affiliation: Department of Medicine 2 and Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.affiliation: Department of Medicine 2 and Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Brand
authors.affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Huelsenbeck
authors.affiliation: Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany; Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D066126:Cardiotoxicity / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D004272:DNA, Mitochondrial; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; C081884:heat-shock protein 70.1; D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor; D004317:Doxorubicin; D008148:Lovastatin
keywords: Anthracyclines; Chronic cardiotoxicity; Doxorubicin; Mitochondrial hyperproliferation; Rho GTPases; Statins