Cardiovascular Research Centre, University of Alberta, Edmonton, Canada.
Cardiovasc Res. 2013 Feb 1;97(2):251-61. doi: 10.1093/cvr/cvs323. Epub 2012 Oct 24.
Infarct-remodelled hearts are less amenable to protection against ischaemia/reperfusion. Understanding preservation of energy metabolism in diseased vs. healthy hearts may help to develop anti-ischaemic strategies effective also in jeopardized myocardium.
Isolated infarct-remodelled/sham Sprague-Dawley rat hearts were perfused in the working mode and subjected to 15 min of ischaemia and 30 min of reperfusion. Protection of post-ischaemic ventricular work was achieved by pharmacological conditioning with sevoflurane. Oxidative metabolism was measured by substrate flux in fatty acid and glucose oxidation using [(3)H]palmitate and [(14)C]glucose. Mitochondrial oxygen consumption was measured in saponin-permeabilized left ventricular muscle fibres. Activity assays of citric acid synthase, hydroxyacyl-CoA dehydrogenase, and pyruvate dehydrogenase and mass spectrometry for acylcarnitine profiling were also performed. Six weeks after coronary artery ligation, the hearts exhibited macroscopic and molecular signs of hypertrophy consistent with remodelling and limited respiratory chain and citric acid cycle capacity. Unprotected remodelled hearts showed a marked decline in palmitate oxidation and acetyl-CoA energy production after ischaemia/reperfusion, which normalized in sevoflurane-protected remodelled hearts. Protected remodelled hearts also showed higher β-oxidation flux as determined by increased oxygen consumption with palmitoylcarnitine/malate in isolated fibres and a lower ratio of C16:1+C16OH/C14 carnitine species, indicative of a higher long-chain hydroxyacyl-CoA dehydrogenase activity. Remodelled hearts exhibited higher PPARα-PGC-1α but defective HIF-1α signalling, and conditioning enabled them to mobilize fatty acids from endogenous triglyceride stores, which closely correlated with improved recovery.
Protected infarct-remodelled hearts secure post-ischaemic energy production by activation of β-oxidation and mobilization of fatty acids from endogenous triglyceride stores.
梗死重构的心脏对缺血/再灌注的保护作用较差。了解疾病和健康心脏的能量代谢保存情况，可能有助于开发在危险心肌中也有效的抗缺血策略。
采用工作模式灌注分离的梗死重构/假手术 Sprague-Dawley 大鼠心脏，并进行 15 分钟缺血和 30 分钟再灌注。用七氟醚进行药物预处理来保护缺血后心室工作。通过用 [(3)H]棕榈酸和 [(14)C]葡萄糖测量脂肪酸和葡萄糖氧化中的底物通量来测量氧化代谢。用皂素通透的左心室肌纤维测量线粒体耗氧量。还进行了柠檬酸合酶、羟酰基辅酶 A 脱氢酶和丙酮酸脱氢酶的活性测定以及酰基辅酶 A 谱的质谱分析。冠状动脉结扎 6 周后，心脏出现与重构一致的宏观和分子肥大迹象，伴有呼吸链和柠檬酸循环能力受限。未受保护的重构心脏在缺血/再灌注后棕榈酸氧化和乙酰辅酶 A 能量产生明显下降，而在七氟醚保护的重构心脏中恢复正常。保护的重构心脏也显示出更高的 β-氧化通量，这通过在分离纤维中增加棕榈酰肉碱/苹果酸的耗氧量来确定，并且 C16:1+C16OH/C14 肉碱种类的比值较低，表明更高的长链羟酰基辅酶 A 脱氢酶活性。重构心脏表现出更高的 PPARα-PGC-1α，但 HIF-1α 信号传导缺陷，预处理使它们能够从内源性甘油三酯储存中动员脂肪酸，这与改善恢复密切相关。
受保护的梗死重构心脏通过激活β-氧化和从内源性甘油三酯储存中动员脂肪酸来确保缺血后的能量产生。
