Peptide amphiphile nanofiber delivery of sonic hedgehog protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection.
Peptide amphiphile nanofiber delivery of sonic hedgehog protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection.
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DOI：
10.1111/j.1743-6109.2010.02001.x
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发表时间：
2011-01
期刊：
影响因子：
--
通讯作者：
Podlasek CA
中科院分区：
文献类型：
--
作者：
Bond CW;Angeloni NL;Harrington DA;Stupp SI;McKenna KE;Podlasek CA
勃起功能障碍（艾德）是一种严重的医学病症，其影响16-82%的通过根治性前列腺切除术治疗的前列腺癌患者，并且目前的治疗在50-60%的前列腺切除术患者中无效。治疗效果的降低使得治疗艾德的新治疗方法变得至关重要。分泌的蛋白质Sonic hedgehog（SHH）是阴茎平滑肌和细胞凋亡的关键调节剂，其在海绵体神经（CN）损伤和糖尿病艾德模型中减少。过去使用Affi-Gel珠的研究表明SHH蛋白可有效抑制CN损伤引起的细胞凋亡。我们推测，SHH蛋白通过新的肽两亲物（PA）纳米纤维传递将有效抑制CN损伤诱导的细胞凋亡。成年Sprague道利大鼠（n = 50）用于优化体内PA注射。将PA与SHH蛋白（n = 16）或牛血清白蛋白（BSA）（对照，n = 14）注射到双侧CN切断的成年大鼠中。在第2、4和7天处死大鼠。使用Alexa Fluor标记的SHH蛋白来确定SHH信号传导的靶标（n = 3）。采用末端脱氧核苷酸转移酶（TUNEL）法检测SHH蛋白和簇分化蛋白3（CD 3）的表达，并进行半定量免疫组化分析。SHH-PA引起CN损伤后4天和7天的细胞凋亡减少25%和16%，SHH蛋白在CN损伤后4天和7天增加9.3%和19%。SHH-PA处理组阴茎未见CD 3蛋白表达。在体外，73%的SHH蛋白在6天内从PA扩散。在平滑肌中观察到标记的SHH。PA技术有效地将SHH蛋白递送至阴茎，并且SHH有效地抑制CN损伤诱导的细胞凋亡。这些结果表明该方法的实质性转化潜力，并表明仅需要短时间的SHH处理来影响凋亡指数。
Erectile dysfunction (ED) is a serious medical condition that affects 16–82% of prostate cancer patients treated by radical prostatectomy and current treatments are ineffective in 50–60% of prostatectomy patients. The reduced efficacy of treatments makes novel therapeutic approaches to treat ED essential. The secreted protein Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle and apoptosis that is decreased in cavernous nerve (CN) injury and diabetic ED models. Past studies using Affi-Gel beads have shown SHH protein to be effective in suppressing apoptosis caused by CN injury. We hypothesize that SHH protein delivered via novel peptide amphiphile (PA) nanofibers will be effective in suppressing CN injury-induced apoptosis. Adult Sprague Dawley rats (n = 50) were used to optimize PA injection in vivo. PA with SHH protein (n = 16) or bovine serum albumin (BSA) (control, n = 14) was injected into adult rats that underwent bilateral CN cut. Rats were sacrificed at 2, 4, and 7 days. Alexa Fluor-labeled SHH protein was used to determine the target of SHH signaling (n = 3). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and semi-quantitative immunohistochemical analysis for SHH protein and cluster differentiation protein three (CD3) were performed. SHH-PA caused a 25% and 16% reduction in apoptosis at 4 and 7 days after CN injury and a 9.3% and 19% increase in SHH protein at 4 and 7 days after CN injury. CD3 protein was not observed in SHH-PA-treated penis. In vitro, 73% of SHH protein diffused from PA within 6 days. Labeled SHH was observed in smooth muscle. PA technology is effective in delivering SHH protein to the penis and SHH is effective in suppressing CN injury-induced apoptosis. These results suggest substantial translational potential of this methodology and show that only a short duration of SHH treatment is required to impact the apoptotic index.
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