Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine.
OBJECTIVE
Previous studies from our laboratory have demonstrated that testosterone increases coronary smooth muscle protein kinase C delta (PKC delta) both in vivo and in vitro and inhibits coronary smooth muscle proliferation by inducing G(0)/G(1) cell cycle arrest in a PKC delta-dependent manner. The purpose of the present study was to determine whether endogenous testosterone limits coronary neointima (NI) formation in a porcine model of post-angioplasty restenosis.


RESULTS
Sexually mature, male Yucatan miniature swine were either left intact (IM), castrated (CM), or castrated with testosterone replacement (CMT; Androgel, 10 mg/day). Angioplasty was performed in both the left anterior descending and left circumflex coronary arteries with balloon catheter overinflation to induce either moderate (1.25-1.3 x diameter; 3 x 30 s) or severe (1.4x diameter; 3 x 30 s) injury, and animals were allowed to recover for either 10 or 28 days. Injured coronary sections were dissected, fixed, stained (Verheoff-Van Gieson, Ki67, PKC delta, p27), and analysed. Vessels without internal elastic laminal rupture were excluded. Following moderate injury, intimal area, intima-to-media ratio (I/M), and I/M normalized to rupture index (RI) were increased in CM compared with IM and CMT. RI, medial area, and intimal/medial thickness (IMT) were not different between groups. NI formation was inversely related to serum testosterone concentration. Conversely, following severe injury, there were no significant differences between the groups. Testosterone inhibited proliferation and stimulated PKC delta and p27(kip1) expression during NI formation (10 days post-injury).


CONCLUSIONS
These findings demonstrate that endogenous testosterone limits coronary NI formation in male swine and provides support for a protective role for testosterone in coronary vasculoproliferative diseases, such as restenosis and atherosclerosis.
Tharp
Darla L
DL
Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
Masseau
Isabelle
I
Ivey
Jan
J
Ganjam
Venkataseshu K
VK
Bowles
Douglas K
DK
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D049109:Cell Proliferation; D023903:Coronary Restenosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009919:Orchiectomy; D051745:Protein Kinase C-delta / Q000378:metabolism; D012720:Severity of Illness Index; D013552:Swine; D013556:Swine, Miniature; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D050760:Cyclin-Dependent Kinase Inhibitor p27; D013739:Testosterone; D051745:Protein Kinase C-delta