Pei-Ying Pai1,2, Yi-Yuan Lin3, Chih-Yang Huang4,5,6, Shin-Da Lee7,8,9,10, Shao-Hong Yu11, Ching-Yuang Lin1,12, Yi-Fan Liou2, Xu-Bo Wu13,14, James K S Wong15. 1. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. 2. Division of Cardiology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan. 3. Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan. 4. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan. 5. Department of Biotechnology, Asia University, Taichung, Taiwan. 6. Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. 7. Department of Rehabilitation, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. shinda@mail.cmu.edu.tw. 8. School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China. shinda@mail.cmu.edu.tw. 9. Department of Physical Therapy, Asia University, Taichung, Taiwan. shinda@mail.cmu.edu.tw. 10. Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taichung, 40402, Taiwan. shinda@mail.cmu.edu.tw. 11. College of Rehabilitation, Shandong University of Traditional Chinese Medicine, Shandong, China. 12. Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan. 13. Department of Rehabilitation, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. 14. School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 15. Department of Cardiology, Asia University Hospital, Taichung, Taiwan.
Abstract
BACKGROUND: The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)-induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis. METHODS: Sprague-Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured in the left ventricle. RESULTS: Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G. CONCLUSIONS: Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea-enhanced cardiac apoptosis via enhancing survival pathways.
BACKGROUND: The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)-induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis. METHODS: Sprague-Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured in the left ventricle. RESULTS: Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G. CONCLUSIONS: Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea-enhanced cardiac apoptosis via enhancing survival pathways.