Rice Kevin M, Desai Devashish H, Kakarla Sunil K, Katta Anjaiah, Preston Deborah L, Wehner Paulette, Blough Eric R
Department of Pharmacology, Physiology and Toxicology, Joan C, Edwards School of Medicine, Marshall University, Huntington, WV, USA.
Cardiovasc Diabetol. 2006 Sep 8;5:18. doi: 10.1186/1475-2840-5-18.
Diabetes mellitus is an important risk factor for increased vein graft failure after bypass surgery. However, the cellular and molecular mechanism(s) underlying vessel attrition in this population remain largely unexplored. Recent reports have suggested that the pathological remodeling of vein grafts may be mediated by mechanically-induced activation of the mitogen activated protein kinase (MAPK) signaling pathways and the MAPK-related induction of caspase-3 activity. On the basis of these findings, we hypothesized that diabetes may be associated with alterations in how veins "sense" and "respond" to altered mechanical loading.
Inferior venae cavae (IVC) from the non-diabetic lean (LNZ) and the diabetic obese (OSXZ) Zucker rats were isolated and incubated ex vivo under basal or pressurized conditions (120 mmHg). Protein expression, basal activation and the ability of increased pressure to activate MAPK pathways and apoptosis-related signaling was evaluated by immunoblot analysis.
Immunoblot analyses revealed differential expression and activation of extracellular signal-regulated kinase (ERK1/2), p38 and c-Jun NH2-terminal kinase (JNK) MAPKs in the IVCs of diabetic rats as compared to non-diabetic rats. In particular, the expression and basal phosphorylation of p38beta- (52.3 +/- 11.8%; 45.8 +/- 18.2%), JNK 1- (21.5 +/- 9.3%; 19.4 +/- 11.6%) and JNK3-MAPK (16.8 +/- 3.3%; 29.5 +/- 17.6%) were significantly higher (P < 0.05) in the diabetic vena cava. An acute increase in IVC intraluminal pressure failed to increase the phosphorylation of ERK1-, JNK-2, or any of the p38-MAPKs in the diabetic obese Zucker rats. Also, IVC loading in the LNZ led to a 276.0 +/- 36.0% and 85.8 +/- 25.1% (P < 0.05) increase in the cleavage of caspase-3 and caspase-9, respectively, with no effect on these molecules in the OSXZ. No differences were found in the regulation of Bax and Bcl-2 between groups. However, basal expression levels of Akt, phospho-Akt, PTEN, phospho-PTEN and phospho-Bad were higher in the diabetic venae cavae (P < 0.05).
These data suggest that diabetes is associated with significant alteration in the ability of the vena cava to activate MAPK- and apoptosis-related signaling. Whether these changes are associated with the increased vein graft attrition seen in the diabetic population will require further investigation.
糖尿病是旁路手术后静脉移植物失败风险增加的重要危险因素。然而，该人群血管损耗的细胞和分子机制在很大程度上仍未得到探索。最近的报告表明，静脉移植物的病理重塑可能由丝裂原活化蛋白激酶（MAPK）信号通路的机械诱导激活以及MAPK相关的半胱天冬酶-3活性诱导介导。基于这些发现，我们推测糖尿病可能与静脉“感知”和“响应”机械负荷改变的方式改变有关。
从非糖尿病瘦型（LNZ）和糖尿病肥胖型（OSXZ）Zucker大鼠分离下腔静脉（IVC），并在基础或加压条件（120 mmHg）下进行离体培养。通过免疫印迹分析评估蛋白表达、基础激活以及压力增加激活MAPK通路和凋亡相关信号的能力。
免疫印迹分析显示，与非糖尿病大鼠相比，糖尿病大鼠IVC中细胞外信号调节激酶（ERK1/2）、p38和c-Jun NH2末端激酶（JNK）MAPK的表达和激活存在差异。特别是，糖尿病腔静脉中p38β-（52.3±11.8%；45.8±18.2%）、JNK 1-（21.5±9.3%；19.4±11.6%）和JNK3-MAPK（16.8±3.3%；29.5±17.6%）的表达和基础磷酸化显著更高（P<0.05）。糖尿病肥胖型Zucker大鼠IVC腔内压力的急性增加未能增加ERK1-、JNK-2或任何p38-MAPK的磷酸化。此外，LNZ中的IVC负荷分别导致半胱天冬酶-3和半胱天冬酶-9的裂解增加276.0±36.0%和85.8±25.1%（P<0.05），而对OSXZ中的这些分子无影响。两组之间Bax和Bcl-2的调节未发现差异。然而，糖尿病腔静脉中Akt、磷酸化Akt、PTEN、磷酸化PTEN和磷酸化Bad的基础表达水平更高（P<0.05）。
这些数据表明，糖尿病与腔静脉激活MAPK和凋亡相关信号的能力显著改变有关。这些变化是否与糖尿病患者中静脉移植物损耗增加有关，需要进一步研究。
