TY - JOUR
T1 - Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart
AU - Park, Min
AU - Nishimura, Takanori
AU - Baeza-Garza, Carlos D.
AU - Caldwell, Stuart T.
AU - Pun, Pamela Boon Li
AU - Prag, Hiran A.
AU - Young, Tim
AU - Sauchanka, Olga
AU - Logan, Angela
AU - Forkink, Marleen
AU - Gruszczyk, Anja V.
AU - Prime, Tracy A.
AU - Arndt, Sabine
AU - Naudi, Alba
AU - Pamplona, Reinald
AU - Coughlan, Melinda T.
AU - Tate, Mitchel
AU - Ritchie, Rebecca H.
AU - Caicci, Federico
AU - Kaludercic, Nina
AU - Di Lisa, Fabio
AU - Smith, Robin A.J.
AU - Hartley, Richard C.
AU - Murphy, Michael P.
AU - Krieg, Thomas
PY - 2020/12
Y1 - 2020/12
N2 - Purpose: HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide. Methods and Results: A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group. Conclusion: Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.
AB - Purpose: HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide. Methods and Results: A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group. Conclusion: Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.
KW - Advanced glycation endproducts (AGE)
KW - Akita mice
KW - Diabetes
KW - Heart failure with preserved ejection fraction (HFpEF)
KW - Mitochondria
UR - http://www.scopus.com/inward/record.url?scp=85091531539&partnerID=8YFLogxK
U2 - 10.1007/s10557-020-07086-7
DO - 10.1007/s10557-020-07086-7
M3 - Article
C2 - 32979176
AN - SCOPUS:85091531539
SN - 0920-3206
VL - 34
SP - 823
EP - 834
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
IS - 6
ER -
