Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice |
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| Affiliation: | 1. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;2. Duke Clinical Research Institute, Durham, NC;3. Athena Institute, VU University, Amsterdam, the Netherlands;4. Cardiology Department, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy;5. Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, New York City, NY;6. The Hatter Cardiovascular Institute, University College London, London, United Kingdom;7. Deutsches Herzzentrum TU München, Munich, Germany;8. LUNAM Université, Université Angers, Laboratoire Cardioprotection Remodelage Thrombose, CHU Angers, France;9. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea;10. First Department of Internal Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan;1. Toxicology Department, Mansoura University, Egypt;2. Clinical Pharmacology Dept, Menoufia Medical School, Menoufia University, Egypt;1. Hospital Care Research Unit, Hyogo Prefectural Amagasaki General Medical Center, Higashinaniwa-cho 2-17-77, Amagasaki 660-8550 Japan;2. Department of Community Medicine in the Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;3. Systematic Review Workshop Peer Support Group (SRWS-PSG), Japan;4. Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Higashinaniwa-cho 2-17-77, Amagasaki 660-8550 Japan;5. Department of Gynecology, Women''s Center, Yotsuya Medical Cube, 7-7, Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan;6. Department of Physical Therapy, School of Health Sciences at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa-shi, Fukuoka 831-8501, Japan;7. Department of Healthcare Epidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;8. Department of Nephrology and Dialysis, Kyoritsu Hospital, 16-5 Chuo-cho, Kawanishi, Hyogo 666-0016, Japan;9. Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine / School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan |
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| Abstract: | Diabetic patients exhibit increased risk for the development of cardiovascular diseases primarily because of impaired nitric oxide (NO) bioavailability. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil restores NO signaling and protects against ischemia/reperfusion (I/R) injury. In this study, we determined the effect of the long-acting PDE-5 inhibitor tadalafil on diabetes-associated complications and its role in attenuating oxidative stress after I/R injury in type 2 diabetic db/db mice. Adult male db/db mice (n=40/group) were randomized to receive dimethyl sulfoxide (10% DMSO, 0.2 ml, ip) or tadalafil (1 mg/kg in 10% DMSO, ip) for 28 days. After 28 days treatment, the hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in the Langendorff mode. Infarct size was measured using computer morphometry of tetrazolium-stained sections. Cardiomyocytes were isolated from a subset of hearts and subjected to 40 min simulated ischemia followed by 1 h of reoxygenation (SI/RO). Dichlorodihydrofluorescein diacetate and JC-1 staining was used to measure reactive oxygen species (ROS) generation and mitochondrial membrane potential (Δψm), respectively. Another subset of hearts was used for the estimation of lipid peroxidation, glutathione, and the expression of myocardial pRac1, Rac1, gp91phox, p47phox, and p67phox by Western blot. Tadalafil treatment improved the metabolic status and reduced infarct size compared to the untreated db/db mice (21.2±1.8% vs 45.8±2.8%; p<0.01). The db/db mice showed enhanced oxidative stress in cardiomyocytes as indicated by a significant increase in ROS production. Cardiac NAD(P)H oxidase activity, lipid peroxidation, and oxidized glutathione were also increased in db/db mice compared to nondiabetic control animals. Tadalafil treatment in db/db mice suppressed oxidative stress, attenuated myocardial expression of pRac1 and gp91phox, and also preserved the loss of Δψm in cardiomyocytes after SI/RO. In conclusion, these results demonstrate that chronic treatment with tadalafil attenuates oxidative stress and improves mitochondrial integrity while providing powerful cardioprotective effects in type 2 diabetes. |
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