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A Redox Responsive MRI Contrast Agent for the Detection of Oxidative Stress in the Heart
Author(s) -
Schwartz Dean,
Yu Meng,
Goldsmith Christian R,
Beyers Ronald,
Cattley Russell C
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.737.1
Subject(s) - oxidative stress , hydrogen peroxide , cardiotoxicity , reactive oxygen species , chemistry , doxorubicin , anthracycline , superoxide , redox , peroxynitrite , pharmacology , biophysics , toxicity , biochemistry , medicine , chemotherapy , cancer , enzyme , biology , organic chemistry , breast cancer
The over‐production of reactive oxygen species (ROS), known as oxidative stress, has been implicated in many mechanisms of tissue injury. The exact role of ROS remains poorly understood, which has motivated efforts to develop imaging techniques capable of differentiating normal from aberrant biological redox activity. A mononuclear Mn(II) complex with the redox‐active ligand N,N′‐bis(2,5‐dihydroxybenzyl)‐N,N′‐bis(2‐pyridinylmethyl)‐1,2‐ethanediamine (H 4 qtp2) responsive to hydrogen peroxide was synthesized and characterized. The capability of H 4 qtp2 to serve as a MRI contrast agent was assessed by 3T MR T1 relaxometry. The relationship between the concentration of H 4 qtp2 and T1 was linear and consistent with the Mn(II)‐H 4 qtp2 adducts remaining intact in solution. The slope yielded a relaxivity (r1) of 5.27 mM −1 s −1 . The r1 of H 4 qtp2 increased to 7.02 mM −1 s −1 upon the addition of 10 mM hydrogen peroxide. H 4 qtp2 also behaves as a strong anti‐oxidant, as evidenced by its ability to degrade superoxide and serve as a hydrogen atom donor in vitro. We next assessed the ability of this agent to detect oxidative stress in the heart. For these studies, rats were injected with the anthracycline anticancer drug, doxorubicin (DOX, 15 mg/kg i.p.). The clinical use of DOX is limited due to cumulative dose‐dependent irreversible cardiotoxicity that leads to congestive heart failure. The mechanism of toxicity is widely accepted to result from the excess generation of reactive oxygen species (ROS) and the resulting oxidative stress in cardiac myocytes. DOX treated rats displayed prolonged ECG QT intervals but no indications of oxidative‐stress induced lipid peroxidation on days 3 or 7. There was, however, an increase in the expression of a number of antioxidant genes in the heart. For cardiac MRI, rats were anesthetized with isoflurane and MRI was performed using a Siemens actively‐shielded whole body 7T MRI scanner. Dark‐blood, T1‐weighted Cine was performed to quantify cardiac function. T1‐mapping was performed with an inversion recovery Look‐Locker sequence before and after intravenous infusion of the redox‐responsive MRI agent H 4 qtp2 (10 mg/kg i.v.). Ejection fraction in control rats was 60.5 +/− 2.5 % and in DOX rats was 50 +/− 2.8% seven days after DOX administration. The T1 (sec) in the myocardium of control rats was similar before and after infusion of H 4 qtp2. The T1 (sec) decreased by 11.8% in the hearts of DOX‐treated rats whereas there was no change in the T1 in skeletal muscle in these same rats. The data suggest that H 4 qtp2 can be used to detect oxidative stress in the hearts of doxorubicin treated rats. Support or Funding Information Funded in part by Auburn University Research Initiative in Cancer (AURIC).