Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice
Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice
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DOI：
10.1016/j.carpath.2014.03.007
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发表时间：
2014-07-01
影响因子：
3.7
通讯作者：
Simpson, Jeremy A.
中科院分区：
文献类型：
--
作者：
Allwood, Melissa A.;Kinobe, Robert T.;Simpson, Jeremy A.
血红素氧合酶-1（HO-1）是一种应激诱导的细胞保护酶。心力衰竭是一种慢性应激诱导的重塑疾病，通常伴有年龄和高血压等合并症。已知HO-1在急性心肌梗死的情况下具有保护作用。HO-1在心力衰竭中的作用尚不清楚，特别是在压力超负荷的情况下。方法：用α-肌球蛋白重链限制性表达HO-1的小鼠，年龄为1岁。此外，小鼠进行了横向主动脉缩窄（TAC）或注入异丙肾上腺素（ISO）诱导heart failure.Results：HO-1转基因小鼠自发性心力衰竭1年后相比，他们的野生型同窝仔，并表现出加速心脏功能不全2周后TAC。野生型小鼠经历压力超负荷表现出广泛的间质纤维化，这是防止HO-1过表达，但HO-1转基因小鼠毛细血管密度降低，收缩储备，舒张末期压升高。然而，HO-1转基因小鼠有显着减弱ISO诱导的心功能不全，间质纤维化，肥大相比，对照组。ISO处理的HO-1转基因小鼠分离的心肌细胞没有表现出过度挛缩/坏死的证据，并降低了NADH氧化酶activity.Conclusions：HO-1是一种有效的机制，减少急性心肌应激，如过度β-肾上腺素能活性。然而，在我们的年龄和压力超负荷模型中，HO-1在心力衰竭的发展中显示出有害的作用而不是治疗作用。(C)2014年爱思唯尔公司All rights reserved.
Introduction: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme induced by stress. Heart failure is a condition of chronic stress-induced remodeling and is often accompanied by comorbidities such as age and hypertension. HO-1 is known to be protective in the setting of acute myocardial infarction. The role of HO-1 in heart failure is not known, particularly in the setting of pressure overload.Methods: Mice with alpha-myosin heavy chain restricted expression of HO-1 were aged for 1 year. In addition, mice underwent transverse aortic constriction (TAC) or were infused with isoproterenol (ISO) to induce heart failure.Results: HO-1 transgenic mice developed spontaneous heart failure after 1 year compared to their wild-type littermates and showed accelerated cardiac dysfunction 2 weeks following TAC. Wild-type mice undergoing pressure overload demonstrated extensive interstitial fibrosis that was prevented by HO-1 overexpression, yet HO-1 transgenic mice had reduced capillary density, contractile reserve, and elevated end-diastolic pressure. However, HO-1 transgenic mice had significantly attenuated ISO-induced cardiac dysfunction, interstitial fibrosis, and hypertrophy compared to control. Isolated cardiomyocytes from HO-1 transgenic mice treated with ISO did not show evidence of hypercontracture/necrosis and had reduced NADH oxidase activity.Conclusions: HO-1 is an effective mechanism for reducing acute myocardial stress such as excess beta-adrenergic activity. However, in our age and pressure overload models, HO-1 showed detrimental rather than therapeutic effects in the development of heart failure. (C) 2014 Elsevier Inc. All rights reserved.