TitleOxidant-induced injury in the mammalian myocardium
NameJaques, Kathryn Michelle (author), Weiss, Harvey (chair), Denhardt, David (internal member), Ma, Jianjie (internal member), Merrill, Gary (internal member), Leone, Richard (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectPhysiology and Integrative Biology,
DescriptionFor over 100 years, acetaminophen (APAP) has been exclusively used as an efficacious antipyretic and analgesic. Here we report our ongoing investigation of the cardiovascular effects of APAP. In the first part of this study, we investigated the effects of 15 mg/kg APAP on hydrogen peroxide (H2O2)-induced canine myocardial dysfunction in vivo. Respiratory, metabolic, and hemodynamic indices such as left ventricular
function (LVDP and ±dP/dtmax), and percent ectopy were measured in anesthetized, openchest
dogs during intravenous administration of increasing doses of H2O2. Following 6.6 mM H2O2, tissue from the LV was harvested for electron microscopy. APAP-treated dogs regained greater fraction of baseline function after high concentrations of H2O2.
Moreover, the incidence of H2O2 -induced ventricular arrhythmias was reduced in APAP treated dogs. Additionally, electron micrograph images of left ventricular tissue confirmed preservation of tissue ultrastructure in APAP-treated hearts. In the second part of this study, we investigated the effects of APAP on
doxorubicin (DOX)-induced murine cardiac fibrosis in vivo, with a more detailed investigation of osteopontin (OPN) involvement using the H9c2 myocyte cell line in
vitro. We hypothesized that APAP would attenuate DOX-induced reactive oxygen species (ROS) and subsequent fibrosis via attenuation of increased cardiomyocyte OPN synthesis. In H9c2 cells, we found a dose-dependent decrease in cell viability at all
concentrations of DOX, which was attenuated by 50 μM APAP. Increased ROS was observed at all concentrations of DOX, which also was attenuated by APAP. A trend of DOX-induced increased OPN RNA synthesis was observed, and was significantly
decreased in the presence of APAP. Additionally, in WT and OPN-/- mice receiving four weekly injections of 4 mg/kg DOX ± APAP (30 mg/kg), we found increased fibrosis in groups receiving DOX as compared to those receiving DOX + APAP. Furthermore,
fibrosis in WT mice was higher than OPN-/- mice after DOX. Our results support the following conclusions: APAP is protective against (1) H2O2 –induced canine myocardial dysfunction, (2) H2O2 –induced arrhythmias, and (3) DOX injury by decreasing ROS, and
(4) lowering OPN RNA synthesis. (5) The absence OPN and presence of APAP decrease the severity of myocardial fibrosis due to DOX injury.
NoteIncludes bibliographical references
Noteby Kathryn Michelle Jaques
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.