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The role of advanced glycation end products on sarcoplasmic reticulum calcium handling during diabetic cardiomyopathy

Kranstuber, Allyson Leigh
http://rave.ohiolink.edu/etdc/view?acc_num=osu1346939589

Abstract Details

2012, Master of Science, Ohio State University, Animal Sciences.
Diabetic heart disease, also called diabetic cardiomyopathy, has been identified as its own clinical identity. Diabetic cardiomyopathy can lead to heart failure, killing ~65% of the patient population, and sudden death. Although we know that impaired calcium (Ca2+) homeostasis is an important factor underlying diabetic cardiomyopathy, the exact mechanisms underlying impaired excitation-contraction are unknown. Our laboratory has previously demonstrated that impaired sarcoplasmic reticulum Ca2+ATPase (SERCA2a) pump underlies diabetic cardiomyopathy. In addition, during diabetes, long-term hyperglycemia leads to the formation of advanced glycation end products (AGE) on sarcoplasmic reticulum (SR) Ca2+ regulatory proteins, which could impair their function and induce diastolic dysfunction, which is characterized by an impaired relaxation of the myocardium. Therefore, we investigated whether the formation of AGEs during diabetes impairs SR Ca2+ reuptake causing the impaired relaxation. We also investigated whether an AGE cross-link breaker, Alagebrium Chloride (ALT-711), could prevent these alterations in SR Ca2+ cycling and restore cardiac function. Groups of low dose streptozotocin (STZ)-induced diabetic rats were treated or not treated with ALT-711 for 8 weeks and compared to age-matched control rats. Venous blood glucose was measured to assess hyperglycemia at baseline and weekly after injection of STZ. Echocardiography was done at baseline and post 8 weeks to assess cardiac function. After 8 weeks of diabetes, either pressure-volume loops were performed to assess cardiomyopathy or cardiac myocytes were isolated to measure Ca2+ transients and SR Ca2+ content. SR Ca2+ regulatory proteins, SERCA2a and ryanodine receptor (RyR2), expression was also measured by Western blot analysis. As expected, hyperglycemia was seen in diabetic rats compared to controls within 72 hours after the injection of STZ. There was no significant difference in blood glucose concentration between treated and non-treated diabetic rats. SR Ca2+ regulatory protein expression, both SERCA2a and RyR2, were significantly decreased in untreated diabetic compared to control groups(P< 0.05), but no significant difference was seen with the diabetic treated group compared to controls. Diastolic dysfunction was shown in the diabetic rats through pressure-volume loops and echocardiography proving that diabetic cardiomyopathy does occur in diabetes. Isovolumic relaxation time (IVRT) and myocardial performance index (MPI) improved with treatment of ALT-711 compared to the untreated diabetic rats (P< 0.05). Ca2+ transient and SR Ca2+ load were significantly decreased with diabetes (P< 0.05) and an improvement was seen with treatment of ALT-711. These data suggest that in our model of type 1 diabetes, AGE accumulation impairs the SERCA2a pump reuptake and that long-term treatment with an AGE cross-link breaker will partially repair cardiac function and SR Ca2+ handling during diabetic cardiomyopathy.
Joseph Ottobre, PhD (Advisor)
Veronique Lacombe, DVM, PhD (Advisor)
Robert Hamlin, DVM, PhD (Committee Member)
72 p.
Physiology
diabetes; diabetic cardiomyopathy; advanced glycation end products; ALT-711

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Citations

  • Kranstuber, A. L. (2012). The role of advanced glycation end products on sarcoplasmic reticulum calcium handling during diabetic cardiomyopathy [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1346939589

    APA Style (7th edition)

  • Kranstuber, Allyson. The role of advanced glycation end products on sarcoplasmic reticulum calcium handling during diabetic cardiomyopathy. 2012. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1346939589.

    MLA Style (8th edition)

  • Kranstuber, Allyson. "The role of advanced glycation end products on sarcoplasmic reticulum calcium handling during diabetic cardiomyopathy." Master's thesis, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1346939589

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.