Presentation Authors: Elizabeth Kalmanek, Shawn Choe, Chicago, IL, Daniel Harrington, Houston, TX, Samuel Stupp, Kevin McVary, Carol Podlasek*, Chicago, IL
Introduction: Erectile dysfunction (ED) affects ~50% of men aged 40-70 and has a high impact on men&[prime]s health. Current treatments are ineffective in the difficult to treat prostatectomy (16-82%) and diabetic (56-59%) patients due to injury to the cavernous nerve (CN). With denervation the critical smooth muscle (SM) undergoes apoptosis and the penis becomes fibrotic, thus altering the corpora cavernosal architecture. In order to devise novel ED therapies, prevention of corpora cavernosal remodeling is critical. Apoptosis can take place via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway. We examine the mechanism of how apoptosis occurs in ED patients and in a CN injury rat model, to determine points of apoptosis intervention for therapy development.
Methods: Immunohistochemical analysis for caspase 3 cleaved, -8 and -9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie&[prime]s, prostatectomy and diabetic ED patients (n=30), and in penis from adult Sprague Dawley rats that underwent CN crush and were sacrificed after 1-9 days (n=16).
Results: Caspase 3 cleaved was observed in corpora cavernosa from Peyronie&[prime]s patients, and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3 cleaved was abundant from 1-9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosal tissue. Caspase 8 staining was observed initially at low abundance in the rat corpora cavernosa, and was not observed at later time points after CN injury (4 and 9 day).
Conclusions: Apoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients, and via the intrinsic caspase 9 dependent pathway in the commonly used CN crush ED rat model. This is significant when considering points of intervention to suppress the apoptotic response to CN injury. Further study is required to determine if differences in rat and human ED apoptotic pathways derives from age of the tissues under study, since ED patients undergoing prosthesis implant to treat their ED, are typically older than commonly used rat ED models.
Source of Funding: NIH/NIDDK DK101536