Mitochondrial Targeted Therapies to Prevent Maternal Diabetes-Induced Congenital Heart Defects.
Mitochondrial Targeted Therapies to Prevent Maternal Diabetes-Induced Congenital Heart Defects.
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线粒体靶向治疗可预防孕产妇糖尿病引起的先天性心脏缺陷。
DOI：
10.1016/j.jacbts.2024.01.016
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Reddy,Sushma
中科院分区：
文献类型：
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作者：
Reddy,Sushma
美国是高收入国家中婴儿死亡率最高的国家，每千名活产婴儿死亡率为5.4%。出生缺陷是婴儿死亡的主要原因。先天性心脏缺陷（CHD）是最常见的出生缺陷类型，约占美国和全球出生缺陷相关死亡率的40%。1这些死亡大多发生在婴儿期，尽管在儿科心脏病学和心脏手术方面取得了巨大进步，但在过去的20年中，这一情况没有发生显著变化。在系统层面上，种族/民族差异，获得优质护理，保险状况和社会经济地位都在CHD相关死亡中发挥关键作用。因此，降低冠心病发病率应纳入降低冠心病相关死亡率的总体解决方案。冠心病的病因可能是多因素的，有遗传（< 10%）和非遗传性危险因素。环境致畸剂如某些药物（沙利度胺、异维甲酸和锂）、病毒感染如母体风疹、母体暴露于吸烟和酒精、母体营养不良（包括叶酸和维生素B 9缺乏症）以及慢性疾病如母体糖尿病和肥胖导致CHD发生的非遗传风险，并为降低CHD发病率提供了潜在的解决方案。2母亲妊娠前糖尿病是CHD唯一相对普遍的人群危险因素，与胎儿CHD风险显著增加相关（校正相对风险：4.0; 95%CI：3.51-4.53）。3有糖尿病相关并发症的女性比无并发症的糖尿病女性有更高的CHD风险（相对风险：7.62 vs 3.49）。尽管产前护理和最佳糖尿病控制的改善，孕前糖尿病相关的CHD的发病率没有改变，在几十年来，突出需要更好地了解因果mechanism.Experimental数据点高血糖在早期胚胎发生改变基因表达的关键细胞组成部分的发展心脏，如流出道。基因表达改变的潜在机制现在才被揭开。糖尿病动物模型显示参与心脏神经嵴细胞代谢、发育和增殖的基因下调。这种基因下调是由高血糖诱导的氧化应激介导的，然后损害配对盒3介导的心脏神经嵴迁移流出道分隔。除了高血糖诱导的氧化应激外，母体糖尿病患者的主要活性氧（ROS）清除酶和抗氧化酶水平也降低，导致早期胚胎发生期间的细胞应激和损伤，这表明葡萄糖的致畸性部分由氧化应激介导。由于线粒体是氧化应激的最大来源和靶点，一些研究小组已经研究了线粒体在胚胎心脏发育中的作用。在胚胎发育期间平衡的线粒体动力学对于维持心脏代谢的变化至关重要，特别是在需要能量的细胞如心肌细胞中。线粒体融合因子2（mitofusin 2，MFN 2）和视神经萎缩是分化的必要条件
The United States has the highest infant mortality rate among high-income countries at 5.4% per 1,000 live births. Birth defects are a major cause of infant mortality. Congenital heart defects (CHDs) are the most common type of birth defect and accounts for about 40% of birth defect–related mortalities in the United States and worldwide. 1 Most of these deaths occur during infancy, and this has not changed significantly in the past 2 decades despite the dramatic improvements seen in pediatric cardiology and cardiac surgery. At a systemic level, racial/ethnic disparities, access to quality care, insurance status, and socioeconomic status all play a key role in CHD-related deaths. Reducing the incidence of CHDs should therefore be factored into the overall solutions to reduce CHD-related mortality. The etiology of CHDs is likely multifactorial, with genetic (< 10%) and noninherited risk factors. Environmental teratogens such as certain medications (thalidomide, isotretinoin, and lithium), viral infections such as maternal rubella, maternal exposure to smoking and alcohol, maternal malnutrition including folic acid and vitamin B9 deficiency, and chronic diseases such as maternal diabetes and obesity contribute to the noninherited risk for developing CHDs and pose a potential solution to decreasing the incidence of CHDs. 2 Maternal pregestational diabetes mellitus is the only relatively prevalent population risk factor for CHDs, associated with a profoundly increased risk for CHDs in the fetus (adjusted relative risk: 4.0; 95% CI: 3.51-4.53). 3 Women with diabetes-related complications have a higher CHD risk than women with diabetes without complications (relative risk: 7.62 vs 3.49). Despite improvements in prenatal care and optimal diabetes control, the incidence of pregestational diabetes-related CHDs has not changed in many decades, highlighting the need to better understand the causal mechanisms.Experimental data point to hyperglycemia during early embryogenesis altering gene expression in key cellular components of the developing heart, such as the outflow tracts. The mechanisms underlying altered gene expression are only now being unraveled. Diabetic animal models demonstrate the downregulation of genes involved in metabolism, development, and proliferation of cardiac neural crest cells. This down-regulation of genes is mediated by hyperglycemia-induced oxidative stress, which then impairs paired box 3–mediated cardiac neural crest migration for outflow tract septation. In addition to hyperglycemia-induced oxidative stress, major reactive oxygen species (ROS) scavenging enzymes and antioxidant enzyme levels are also decreased in maternal diabetes, leading to cellular stress and damage during early embryogenesis, suggesting that the teratogenicity of glucose is mediated, in part, by oxidative stress. As mitochondria are the largest source and targets of oxidative stress, several groups have investigated the role of mitochondria in embryonic heart development. Balanced mitochondrial dynamics during embryonic development are critical to sustain the changes in heart metabolism, especially in energy-demanding cells such as cardiomyocytes. The mitochondrial fusion factors, mitofusin 2 (MFN2) and optic atrophy are essential for the differentiation