Osanai T, Kanazawa T, Okuguchi T, Kamada T, Metoki H, Oike Y, Onodera K
Second Department of Internal Medicine, Hirosaki University School of Medicine, Japan.
Cardiovasc Res. 1996 Jan;31(1):124-31.
Vasoconstrictor peptides such as endothelin (ET) cause hypertrophy of vascular smooth muscle cells (VSMC) in Wistar Kyoto rats (WKY) and hyperplasia in spontaneously hypertensive rats (SHR). They also induce an increase in Na+ concentration ([Na+]i) and activate protein kinase C (PKC) independently. Therefore, we tested the hypothesis that the increase in [Na+]i may be involved in the conversion of growth manner under activated PKC in SHR VSMC.
10(-7) M phorbol ester (TPA) increased the diameter and protein content of VSMC from both strains under 18% serum conditions. Further addition of 10(-6) M gramicidin (Na+ ionophore) converted TPA-induced hypertrophy to hyperplasia, which was due to the quick transition from S to G2/M phase, only in SHR VSMC. Western blot analysis showed that serum- and TPA-induced tyrosine phosphorylation of mitogen-activated protein (MAP) kinase was potentiated by 10(-6) M gramicidin in SHR. [Na+]i, which was measured by sodium-binding benzofuran isophthalate (SBFI), was increased about 35 mM by 10(-6) M gramicidin in both strains, but TPA did not affect basal [Na+]i and the gramicidin-induced increase in [Na+]i.
We conclude that sodium ionophore may convert hypertrophy to hyperplasia synergistically with activated PKC in SHR VSMC, possibly by MAP kinase phosphorylation.
血管收缩肽如内皮素（ET）可导致Wistar Kyoto大鼠（WKY）的血管平滑肌细胞（VSMC）肥大，以及自发性高血压大鼠（SHR）的血管平滑肌细胞增生。它们还能独立诱导细胞内钠离子浓度（[Na⁺]i）升高并激活蛋白激酶C（PKC）。因此，我们检验了这样一个假设：在SHR的VSMC中，PKC激活状态下[Na⁺]i的升高可能参与生长方式的转变。
在18%血清条件下，10⁻⁷M佛波酯（TPA）增加了两种品系VSMC的直径和蛋白质含量。进一步添加10⁻⁶M短杆菌肽（钠离子载体）后，仅在SHR的VSMC中，将TPA诱导的肥大转变为增生，这是由于细胞从S期快速过渡到G2/M期所致。蛋白质免疫印迹分析显示，在SHR中，10⁻⁶M短杆菌肽增强了血清和TPA诱导的丝裂原活化蛋白（MAP）激酶的酪氨酸磷酸化。通过苯并呋喃异邻苯二甲酸钠（SBFI）测量的[Na⁺]i，在两种品系中均因10⁻⁶M短杆菌肽而增加约35mM，但TPA不影响基础[Na⁺]i以及短杆菌肽诱导的[Na⁺]i升高。
我们得出结论，钠离子载体可能与SHR的VSMC中激活的PKC协同作用，将肥大转变为增生，可能是通过MAP激酶磷酸化实现的。
