Response Gene to Complement 32 Maintains Blood Pressure Homeostasis by Regulating α-Adrenergic Receptor Expression.
Response Gene to Complement 32 Maintains Blood Pressure Homeostasis by Regulating α-Adrenergic Receptor Expression.
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补体 32 的反应基因通过调节 α-肾上腺素能受体表达维持血压稳态
DOI：
10.1161/circresaha.118.313266
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发表时间：
2018-10-12
影响因子：
20.1
通讯作者：
Chen SY
中科院分区：
文献类型：
--
作者：
Tang JM;Shi N;Dong K;Brown SA;Coleman AE;Boegehold MA;Chen SY
与正常出生体重的人相比，低出生体重和产后体重增加较大的儿童和青少年的高血压患病率要高得多。然而，这种并发症的病因和分子机制在很大程度上仍然未知。我们之前的研究表明，与野生型对照相比，补体32缺陷应答基因（RGC-32−/−）小鼠出生时明显更小，但生长速度更快，这使得成年RGC32−/−小鼠的体重与对照小鼠相似。本研究的目的是确定RGC32 - / -小鼠是否会发生高血压，如果会，阐明其潜在机制。通过无线电遥测系统，我们发现RGC-32 - / -小鼠的平均动脉压高于野生型小鼠（101±4 mmHg vs.119±5 mmHg），这使我们能够使用RGC-32 - / -小鼠来研究低出生体重相关高血压的机制。RGC-32 - / -小鼠血压升高与血管张力升高和小阻力动脉扩张性降低有关。血管张力的增加是由于交感神经和副交感神经活动的相对贡献增加，并与动脉平滑肌中血管紧张素II型（AT1R）和α1-肾上腺素能（AdR）受体的表达增加有关。机制上，RGC-32通过与Sp1转录因子相互作用，进一步阻断其与AT1R启动子的结合，从而抑制AT1R基因的表达，从而调控AT1R基因的转录。AT1R的衰减导致α1-AdR表达的降低，这对于平衡交感神经和副交感神经对血管张力的控制至关重要。重要的是，动脉平滑肌中RGC-32的下调也与人类低出生体重和高血压有关。我们的研究结果表明，RGC-32是一种新的蛋白质因子，对维持血压稳态至关重要，特别是在低出生体重的个体中。
Hypertension prevalence is much higher among children and adolescents with low birth weight and greater postnatal weight gain than in individuals with normal birth weight. However, the etiology and molecular mechanisms underlying this complication remain largely unknown. Our previous studies have shown that response gene to complement 32 deficient (RGC-32−/−) mice are born significantly smaller, but grow faster than their wild type controls, which allows adult RGC32−/− mice to attain body weights similar to those of control mice. The objective of this study is to determine if RGC32−/− mice develop hypertension, and if so, to elucidate the underlying mechanisms. By using a radiotelemetry system, we found that RGC-32−/− mice exhibit higher mean arterial pressure than wild-type mice (101 ± 4 mmHg vs.119 ±5 mmHg), which enabled us to use RGC-32−/− mice to study the mechanisms underlying low birth weight-related hypertension. The increased blood pressure in RGC-32−/− mice was associated with increased vascular tone and decreased distensibility of small resistance arteries. The increased vascular tone was due to an increase in the relative contribution of sympathetic versus parasympathetic activity and was linked to increased expression of angiotensin II type I (AT1R) and α1-adrenergic (AdR) receptors in arterial smooth muscles. Mechanistically, RGC-32 regulated AT1R gene transcription by interacting with Sp1 transcription factor and further blocking its binding to the AT1R promoter, leading to suppression of AT1R expression. The attenuation of AT1R led to reduction in α1-AdR expression, which was critical for the balance of sympathetic vs. parasympathetic control of vascular tone. Of importance, down-regulation of RGC-32 in arterial smooth muscles was also associated with low birth weight and hypertension in humans. Our results indicate that RGC-32 is a novel protein factor vital for maintaining blood pressure homeostasis, especially in individuals with low birth weight.