Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart
Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA ut...
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| Vydáno v: | Cardiovascular research Ročník 114; číslo 7; s. 979 |
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| Hlavní autoři: | , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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England
01.06.2018
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| ISSN: | 1755-3245, 1755-3245 |
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| Abstract | Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload.
Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression.
These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF. |
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| AbstractList | Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload.AimsHeart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload.Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression.Methods and resultsTransverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression.These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF.ConclusionsThese findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF. Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload. Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression. These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF. |
| Author | Yang, Hongyan Guo, Yongzheng Xu, Jie Xing, Wenjuan Zhang, Xing Wang, Zhen Li, Xiaoliang Qin, Xinghua Hou, Zuoxu Gao, Feng Mao, Xuechao |
| Author_xml | – sequence: 1 givenname: Yongzheng surname: Guo fullname: Guo, Yongzheng organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 2 givenname: Zhen surname: Wang fullname: Wang, Zhen organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 3 givenname: Xinghua surname: Qin fullname: Qin, Xinghua organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 4 givenname: Jie surname: Xu fullname: Xu, Jie organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 5 givenname: Zuoxu surname: Hou fullname: Hou, Zuoxu organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 6 givenname: Hongyan surname: Yang fullname: Yang, Hongyan organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 7 givenname: Xuechao surname: Mao fullname: Mao, Xuechao organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 8 givenname: Wenjuan surname: Xing fullname: Xing, Wenjuan organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 9 givenname: Xiaoliang surname: Li fullname: Li, Xiaoliang organization: Department of Emergency Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China – sequence: 10 givenname: Xing surname: Zhang fullname: Zhang, Xing organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and – sequence: 11 givenname: Feng surname: Gao fullname: Gao, Feng organization: School of Aerospace Medicine, Fourth Military Medical University, 17 Changlexi Road, Xi'an 710032, China and |
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