Division of Cardiology, Federico II University, Via Pansini 5, 80131 Naples, Italy.
Hypertension. 2010 Jan;55(1):137-43. doi: 10.1161/HYPERTENSIONAHA.109.135467. Epub 2009 Nov 9.
Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure overload, we assayed the activity of MAPKs extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal-regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal-regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.
压力超负荷已被证明可诱导丝裂原活化蛋白激酶（MAPKs）并使心房利钠因子在心脏中重新激活。为了测试这些信号对压力超负荷的敏感性，我们检测了左心室（LV）或从主动脉缩窄小鼠分离的白细胞（WBC）蛋白裂解物中 MAPKs 的活性，这些小鼠的压力超负荷程度不同。在分离的小鼠中，我们通过 Northern 印迹法测量心房利钠因子 mRNA 水平。正如预期的那样，在主动脉缩窄后观察到心房利钠因子 mRNA 水平显著增加，并且它与跨狭窄收缩压梯度显著相关，但与 LV 重量：体重比无关。相比之下，在 LV 样本或 WBC 中检测到的所有 MAPK 活性均与收缩压梯度或 LV 重量：体重比显著相关。重要的是，LV 中 MAPKs 的激活与同一动物的 WBC 中 MAPKs 的激活显著相关。为了测试 WBC 中 MAPK 激活是否可能反映人类不受控制的血压水平，我们检测了从正常血压志愿者、血压控制良好的高血压患者和血压控制不佳的高血压患者中分离出的 WBC 中细胞外信号调节激酶、c-Jun N-末端激酶 1 和 p38 的激活。有趣的是，与血压控制不佳的高血压患者相比，血压控制良好的高血压患者的 LV 质量和细胞外信号调节激酶磷酸化明显降低。这些结果表明 MAPKs 是压力超负荷的传感器，并且 WBC 中的细胞外信号调节激酶激活可能被用作不受控制的人类高血压的新型替代生物标志物。
