Abstract:
:The mitochondrial F1F0 ATP synthase is responsible for the majority of ATP production in mammals and does this through a rotary catalytic mechanism. Studies show that the F1F0 ATP synthase can switch to an ATP hydrolase, and this occurs under conditions seen during myocardial ischemia. This ATP hydrolysis causes wasting of ATP that does not produce work. The degree of ATP inefficiently hydrolyzed during ischemia may be as high as 50-90% of the total. A naturally occurring, reversible inhibitor (IF-1) of the hydrolase activity is in the mitochondria, and it has a pH optimum of 6.8. Based on studies with the nonselective (inhibit both synthase and hydrolase activity) inhibitors aurovertin B and oligomycin B reduce the rate of ATP depletion during ischemia, showing that IF-1 does not completely block hydrolase activity. Oligomycin and aurovertin cannot be used for treating myocardial ischemia as they will reduce ATP production in healthy tissue. We generated a focused structure-activity relationship, and several compounds were identified that selectively inhibited the F1F0 ATP hydrolase activity while having no effect on synthase function. One compound, BMS-199264 had no effect on F1F0 ATP synthase function in submitochondrial particles while inhibiting hydrolase function, unlike oligomycin that inhibits both. BMS-199264 selectively inhibited ATP decline during ischemia while not affecting ATP production in normoxic and reperfused hearts. BMS-191264 also reduced cardiac necrosis and enhanced the recovery of contractile function following reperfusion. These data also suggest that the reversal of the synthase and hydrolase activities is not merely a chemical reaction run in reverse.
journal_name
Cardiovasc Therjournal_title
Cardiovascular therapeuticsauthors
Grover GJ,Malm Jdoi
10.1111/j.1755-5922.2008.00065.xsubject
Has Abstractpub_date
2008-01-01 00:00:00pages
287-96issue
4eissn
1755-5914issn
1755-5922pii
CDR065journal_volume
26pub_type
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journal_title:Cardiovascular therapeutics
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pub_type: 杂志文章,多中心研究,随机对照试验
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pub_type: 杂志文章,评审
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章,meta分析,评审
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更新日期:2014-06-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章,评审
doi:10.1111/j.1755-5922.2010.00214.x
更新日期:2011-06-01 00:00:00
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pub_type: 杂志文章,meta分析,评审
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更新日期:2016-04-01 00:00:00
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pub_type: 杂志文章,meta分析,评审
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更新日期:2014-08-01 00:00:00
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更新日期:2015-12-01 00:00:00
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pub_type: 杂志文章,meta分析
doi:10.1155/2020/3987065
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pub_type: 杂志文章,meta分析
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pub_type: 杂志文章
doi:10.1111/1755-5922.12111
更新日期:2015-04-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章,评审
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
doi:10.1111/1755-5922.12459
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
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更新日期:2017-10-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
doi:10.1111/1755-5922.12181
更新日期:2016-08-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
doi:10.1111/j.1755-5922.2010.00203.x
更新日期:2011-08-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
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更新日期:2016-04-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
doi:10.1111/1755-5922.12027
更新日期:2013-12-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章,评审
doi:10.1111/j.1755-5922.2010.00227.x
更新日期:2012-02-01 00:00:00
abstract::Recent studies have shown that stromal cell derived factor-1 (SDF-1), first known as a cytokine involved in recruiting stem cells into injured organs, confers myocardial protection in myocardial infarction, which is not dependent on stem cell recruitment but related with modulation of ischemia-reperfusion (I/R) injury...
journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
doi:10.1111/j.1755-5922.2011.00301.x
更新日期:2012-10-01 00:00:00
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journal_title:Cardiovascular therapeutics
pub_type: 杂志文章
doi:10.1111/1755-5922.12047
更新日期:2013-12-01 00:00:00