Effects of Altering Mitochondrial Antioxidant Capacity on Molecular and Phenotypic Drivers of Fibrocalcific Aortic Valve Stenosis.
Effects of Altering Mitochondrial Antioxidant Capacity on Molecular and Phenotypic Drivers of Fibrocalcific Aortic Valve Stenosis.
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DOI：
10.3389/fcvm.2021.694881
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发表时间：
2021
影响因子：
3.6
通讯作者：
Miller JD
中科院分区：
文献类型：
--
作者：
Roos CM;Zhang B;Hagler MA;Verzosa GC;Huang R;Oehler EA;Arghami A;Miller JD
背景资料：虽然少数研究表明，氧化应激在纤维钙化性主动脉瓣疾病（FCAVD）中具有重要作用，但对特定抗氧化酶在该疾病进展中的作用仍知之甚少。在这里，我们专注于选择性地改变脑源性氧化应激-这已被证明可以改变无数年龄相关疾病的进展-对FCAVD的分子和表型驱动因素的进展。研究方法：我们产生了低密度脂蛋白受体缺陷、仅载脂蛋白B100的小鼠（LA），这些小鼠要么是MnSOD单倍不足（LA-MnSOD+/−），要么是MnSOD基因过表达（LA-MnSODTg/0）。在西方饮食喂养6个月后，对小鼠进行超声心动图以评估瓣膜和心脏功能，并收获组织。定量RT PCR，免疫组织化学和组织病理学被用来测量氧化应激，钙化和纤维化相关的分子途径的变化。结果如下：虽然MnSOD的减少会增加氧化应激，但MnSOD缺乏对LA-MnSOD+/−小鼠的瓣膜和心脏功能没有明显的表型影响。虽然经典骨形态发生蛋白信号传导的标志物倾向于在LA-MnSOD+/−的瓣膜组织中增加（例如，p-SMAD 1/5/8和osterix），我们没有观察到成骨信号的统计学显著增加。然而，我们确实观察到骨桥蛋白表达的显著降低，这与LA-MnSOD+/−小鼠钙负荷的显著增加有关。反过来，遗传增加MnSOD没有保存LA-MnSODTg/0的瓣膜功能，但我们确实观察到p-SMAD 1/5/8水平与其非转基因同窝仔相比略有下降。有趣的是，MnSOD过表达显著增加了LA-MnSODTg/0小鼠瓣膜组织中骨桥蛋白的表达，但与LA-MnSOD 0/0同窝小鼠相比，不足以减轻钙负荷。结论：总的来说，这项研究表明，在FCAVD小鼠模型中，维持线粒体抗氧化能力对于预防疾病加速进展很重要，但有效改变线粒体抗氧化能力作为减缓FCAVD关键组织病理学和分子驱动因素的一种单药方法仍然具有生物学和治疗挑战性。
Background: While a small number of studies suggest that oxidative stress has an influential role in fibrocalcific aortic valve disease (FCAVD), the roles of specific antioxidant enzymes in progression of this disease remain poorly understood. Here, we focused on selectively altering mitochondrial-derived oxidative stress—which has been shown to alter progression of a myriad of age-associated diseases—on the progression of molecular and phenotypic drivers of FCAVD. Methods: We generated low-density lipoprotein receptor-deficient, Apolipoprotein B100-only mice (LA) that were either haploinsufficient for MnSOD (LA-MnSOD+/−) or genetically overexpressing MnSOD (LA-MnSODTg/0). After 6 months of Western diet feeding, mice underwent echocardiography to assess valvular and cardiac function and tissues were harvested. Quantitative-RT PCR, immunohistochemistry, and histopathology were used to measure changes in molecular pathways related to oxidative stress, calcification, and fibrosis. Results: While reductions in MnSOD increased oxidative stress, there was not an overt phenotypic effect of MnSOD deficiency on valvular and cardiac function in LA-MnSOD+/− mice. While markers of canonical bone morphogenetic protein signaling tended to increase in valve tissue from LA-MnSOD+/− (e.g., p-SMAD1/5/8 and osterix), we did not observe statistically significant increases in osteogenic signaling. We did, however, observe highly significant reductions in expression of osteopontin, which were associated with significant increases in calcium burden in LA-MnSOD+/− mice. Reciprocally, genetically increasing MnSOD did not preserve valve function in LA-MnSODTg/0, but we did observe slight reductions in p-SMAD1/5/8 levels compared to their non-transgenic littermates. Interestingly, overexpression of MnSOD dramatically increased expression of osteopontin in valve tissue from LA-MnSODTg/0 mice, but was not sufficient to attenuate calcium burden when compared to their LA-MnSOD0/0 littermates. Conclusions: Collectively, this study demonstrates that maintenance of mitochondrial antioxidant capacity is important in preventing accelerated disease progression in a mouse model of FCAVD, but that effectively altering mitochondrial antioxidant capacity as a monotherapeutic approach to slow key histopathological and molecular drivers of FCAVD remains biologically and therapeutically challenging.
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影响因子：
24
作者：
Miller, Jordan D.;Chu, Yi;Brooks, Robert M.;Richenbacher, Wayne E.;Pena-Silva, Ricardo;Heistad, Donald D.
通讯作者：
Heistad, Donald D.
DOI：
10.1161/atvbaha.110.211029
发表时间：
2010-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Miller JD;Weiss RM;Serrano KM;Castaneda LE;Brooks RM;Zimmerman K;Heistad DD
通讯作者：
Heistad DD
影响因子：
5.3
作者：
Kakko, S;Päivänsalo, M;Savolainen, MJ
通讯作者：
Savolainen, MJ
DOI：
10.1152/ajpheart.00735.2012
发表时间：
2013-11-01
影响因子：
4.8
作者：
Roos, Carolyn M.;Hagler, Michael;Miller, Jordan D.
通讯作者：
Miller, Jordan D.
影响因子：
1.2
作者：
Casaclang-Verzosa, Grace;Enriquez-Sarano, Maurice;Miller, Jordan D.
通讯作者：
Miller, Jordan D.