Allwood Melissa A, Kinobe Robert T, Ballantyne Laurel, Romanova Nadya, Melo Luis G, Ward Christopher A, Brunt Keith R, Simpson Jeremy A
Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
School of Veterinary & Biomedical Science, James Cook University, 1 James Cook Drive, Townsville, Queensland, 4811, Australia.
Cardiovasc Pathol. 2014 Jul-Aug;23(4):231-7. doi: 10.1016/j.carpath.2014.03.007. Epub 2014 Apr 5.
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.
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.
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.
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.
血红素加氧酶-1（HO-1）是一种由应激诱导产生的细胞保护酶。心力衰竭是一种由慢性应激诱导的重塑状态，常伴有年龄增长和高血压等合并症。已知HO-1在急性心肌梗死情况下具有保护作用。HO-1在心力衰竭中的作用尚不清楚，尤其是在压力超负荷情况下。
α-肌球蛋白重链限制表达HO-1的小鼠饲养1年。此外，对小鼠进行主动脉缩窄（TAC）或注射异丙肾上腺素（ISO）以诱导心力衰竭。
与野生型同窝小鼠相比，HO-1转基因小鼠在1年后出现自发性心力衰竭，并且在TAC后2周显示出加速的心脏功能障碍。经历压力超负荷的野生型小鼠出现广泛的间质纤维化，而HO-1过表达可预防这种情况，但HO-1转基因小鼠的毛细血管密度降低、收缩储备减少且舒张末期压力升高。然而，与对照组相比，HO-1转基因小鼠的ISO诱导的心脏功能障碍、间质纤维化和肥大明显减轻。用ISO处理的HO-1转基因小鼠分离的心肌细胞未显示出过度收缩/坏死的迹象，并且NADH氧化酶活性降低。
HO-1是减轻急性心肌应激（如过量β-肾上腺素能活性）的有效机制。然而，在我们的年龄和压力超负荷模型中，HO-1在心力衰竭发展中显示出有害而非治疗作用。
