Premium
MORPHINE PROTECTS AGAINST CARDIAC DYSFUNCTION DURING TYPE 2 DIABETES BY IMPROVING MITOCHONDRIAL STRUCTURE AND FUNCTION
Author(s) -
ZemljicHarpf Alice Eugenie,
Hoe Louise See,
Schilling Jan Mirko,
Nguyen Alexander,
Vainshav Yash J.,
Peart Jason N.,
Mahata Sushil K.,
Patel Hemal H.,
Headrick John P.
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.1269.4
Subject(s) - medicine , cardiac function curve , endocrinology , diabetic cardiomyopathy , type 2 diabetes , impaired glucose tolerance , diabetes mellitus , cardioprotection , mitophagy , mitochondrial permeability transition pore , mitochondrion , lipotoxicity , heart failure , hyperinsulinemia , ischemia , cardiomyopathy , insulin resistance , biology , autophagy , apoptosis , programmed cell death , microbiology and biotechnology , biochemistry
Diabetes promotes ischemic heart disease, cardiomyopathy, intolerance to ischemia‐reperfusion (I‐R) injury, and refractoriness to cardioprotection. Evidence suggests that cardiac abnormalities during diabetes involve inflammation, lipotoxicity, posttranslational‐modifications as well as mitochondrial dysfunction and impaired opioid receptor (OR) signaling. We test the hypothesis that a novel sustained OR stimulus may overcome diabetes induced cardiac dysfunction via mitochondrial dependent protection. In a murine type 2 diabetes mellitus (T2DM) model we investigated effects of morphine on cardiac function, structure and I‐R tolerance, mitochondrial function and ultrastructure. Streptozotozin (75mg/kg i.p.) was administered once in non‐fasted 12‐week old mice, and normal chow was switched to 60% kcal high‐fat diet (HFD). 12 weeks of HFD induced 25% weight gain, hyperglycemia, hyperinsulinemia, glucose intolerance, cardiac hypertrophy, moderate cardiac depression, exaggerated post‐ischemic myocardial dysfunction and death, and abnormalities in mitochondrial respiration, ultrastructure and Ca 2+ ‐induced swelling. Morphine administration for 5 days: 1) improved glucose homeostasis and body weight; 2) reversed cardiac depression; 3) enhanced I‐R tolerance; 4) restored mitochondrial ultrastructure; and 5) improved mitochondrial function. A treatment‐matched caloric restriction regime modestly improved I‐R tolerance in T2DM mice without improving in vivo cardiac function. These data reveal that morphine treatment restores contractile function and ischemic tolerance in diabetic hearts via improvements in mitochondrial structure and function, implicating OR activation as a potential novel target in managing T2DM‐induced myocardial abnormalities. Support or Funding Information This study was supported by grants from the National Institutes of Health, USA (HL091071, HL107200, HL115933, and HL066941), a VA Merit grant (BX001963 and BX000783), and the National Health and Medical Research Council of Australia (481922).