Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Chongqing Institute of Cardiology and Chongqing Key Laboratory for Hypertension Research, Chongqing, China.
J Am Heart Assoc. 2018 Jan 7;7(1):e007185. doi: 10.1161/JAHA.117.007185.
Epidemiological evidence supports an important association between air pollution exposure and hypertension. However, the mechanisms are not clear.
Our present study found that long-term exposure to fine particulate matter (PM) causes hypertension and impairs renal sodium excretion, which might be ascribed to lower D receptor expression and higher D receptor phosphorylation, accompanied with a higher G-protein-coupled receptor kinase type 4 (GRK4) expression. The in vivo results were confirmed in in vitro studies (ie, PM increased basal and decreased D receptor mediated inhibitory effect on Na-K ATPase activity, decreased D receptor expression, and increased D receptor phosphorylation in renal proximal tubule cells). The downregulation of D receptor expression and function might be attributable to a higher GRK4 expression after the exposure of renal proximal tubule cells to PM, because downregulation of GRK4 by small-interfering RNA reversed the D receptor expression and function. Because of the role of reactive oxygen species on D receptor dysfunction and its relationship with air pollution exposure, we determined plasma reactive oxygen species and found the levels higher in PM-treated Sprague-Dawley rats. Inhibition of reactive oxygen species by tempol (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) reduced blood pressure and increased sodium excretion in PM-treated Sprague-Dawley rats, accompanied by an increase in the low D receptor expression, and decreased the hyperphosphorylated D receptor and GRK4 expression.
Our present study indicated that long-term exposure of PM increases blood pressure by decreasing D receptor expression and function; reactive oxygen species, via regulation of GRK4 expression, plays an important role in the pathogenesis of PM-induced hypertension.
流行病学证据支持空气污染暴露与高血压之间存在重要关联。然而，其机制尚不清楚。
我们目前的研究发现，长期暴露于细颗粒物（PM）会导致高血压并损害肾脏钠排泄，这可能归因于 D 受体表达降低和 D 受体磷酸化增加，同时伴有 G 蛋白偶联受体激酶 4（GRK4）表达升高。体内研究结果在体外研究中得到了证实（即 PM 增加了基础状态下和降低了 D 受体介导的对 Na-K ATP 酶活性的抑制作用，降低了 D 受体表达，增加了肾近端小管细胞中的 D 受体磷酸化）。D 受体表达和功能的下调可能归因于肾近端小管细胞暴露于 PM 后 GRK4 表达升高，因为通过小干扰 RNA 下调 GRK4 可逆转 D 受体表达和功能。由于活性氧在 D 受体功能障碍中的作用及其与空气污染暴露的关系，我们测定了血浆活性氧水平，发现 PM 处理的 Sprague-Dawley 大鼠中的水平更高。通过 tempol（4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基）抑制活性氧可降低 PM 处理的 Sprague-Dawley 大鼠的血压并增加钠排泄，同时增加低 D 受体表达，减少高磷酸化 D 受体和 GRK4 表达。
我们目前的研究表明，长期 PM 暴露通过降低 D 受体表达和功能来增加血压；活性氧通过调节 GRK4 表达在 PM 诱导的高血压发病机制中发挥重要作用。
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