Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA.
J Sex Med. 2011 Dec;8(12):3335-44. doi: 10.1111/j.1743-6109.2011.02499.x. Epub 2011 Oct 13.
Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known.
We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice.
The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10(-5) M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10(-4) M]).
Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0 ± 5% vs. 82.5 ± 7%) and nitrergic stimulation (27 ± 2% vs. 76 ± 6%) by electrical field stimulation (EFS, 1-32 Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27 ± 2% vs. 60 ± 4%) and endothelium-dependent relaxation responses (38.0 ± 5% vs. 67.5 ± 6%). Acute treatment with the arginase inhibitor BEC (10(-4) M) also improves EFS-induced relaxation in diabetic mice (31 ± 3% vs. 49 ± 2%). Moreover, vascular expression of activated ERK was increased in diabetic over control mice.
These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.
研究发现，精氨酸酶（AA）活性增加会减少 L-精氨酸的可用性和一氧化氮的产生，从而导致高血压和糖尿病引起的内皮功能障碍。与没有勃起功能障碍（ED）的患者相比，ED 患者的细胞外信号调节激酶（ERK）的活性更高。已经有报道称，ERK 和精氨酸酶都会影响一氧化氮合酶（NOS）的表达和活性，从而影响阴茎勃起。然而，ERK 在阴茎中激活的信号通路还不是很清楚。
我们假设 ERK 抑制剂 PD98059 抑制 ERK 的激活可以降低 AA 的活性，从而改善链脲佐菌素（STZ）诱导的糖尿病小鼠的海绵体松弛。
通过 Western blot 检测 AA、ERK、eNOS 以及精氨酸酶 I 和 II 的表达，并测定海绵体组织的功能反应。对照组和糖尿病组的海绵体组织先用 PD98059（10(-5) M）和精氨酸酶抑制剂（（S）-（2-硼代乙基）-L-半胱氨酸盐酸盐，[BEC]10(-4) M）预处理。
糖尿病小鼠的 AA 水平显著升高（增加两倍），而急性 PD98059 处理可阻断这种作用。与对照组相比，糖尿病小鼠的海绵体对内皮依赖性激动剂乙酰胆碱（38.0±5%比 82.5±7%）和氮能刺激（27±2%比 76±6%）的舒张反应（STZ-糖尿病组分别）均降低。然而，PD98059 处理可减轻糖尿病小鼠海绵体松弛的损伤，氮能刺激（27±2%比 60±4%）和内皮依赖性舒张反应（38.0±5%比 67.5±6%）。急性使用精氨酸酶抑制剂 BEC（10(-4) M）也可改善糖尿病小鼠的 EFS 诱导舒张（31±3%比 49±2%）。此外，与对照组相比，糖尿病小鼠的血管中激活的 ERK 表达增加。
这些数据表明，ERK 抑制可防止阴茎 AA 的升高，并可预防糖尿病引起的 ED。
