The herbal extract HMC05 inhibits neointima formation in balloon-injured rat carotid arteries: possible therapeutic implications of HMC05.
OBJECTIVE
In a previous study, HMC05, a water extract from eight medicinal herbs was demonstrated to possess anti-inflammatory effects in murine macrophages and anti-atherosclerotic effects in apoE(-/-) mice. HSP27 expression was shown to be decreased in advanced atherosclerotic plaques of human carotid arteries. In the present study, the role of HMC05 in the prevention of restenosis and the possible mechanisms involved in the decrease of neointima formation were investigated using in vivo balloon injury rat model and in vitro biochemical assays.


METHODS
A rat carotid artery balloon injury restenosis model was used. Different doses of HMC05 were administered to the rats by tube feeding, starting from four days before surgery and continuing twice per week for two weeks after carotid injury. Injured carotid arteries isolated from rats were embedded in paraffin block and tissue sections were stained with H&E to assess neointima formation. Mechanism by HMC05 that are involved in smooth muscle cell proliferation and migration was assessed by western blot assay, immunohistochemistry and confocal analysis.


RESULTS
There was no significant difference in the medial area between the control and HMC05-treated groups. However, neointima formation was significantly inhibited in the HMC05-treated group, resulting in 47-fold lower intima to media ratios in rats treated with 25 mg/kg/day HMC05 as compared to the control. Surprisingly, monocytes infiltration in the neointima area was almost completely blocked by HMC05 administration. When rat vascular SMCs were treated with HMC05, the proliferation and migration of smooth muscle cells was dramatically inhibited in a dye uptake assay and in a scratch model in a culture dish, respectively. HMC05 dose-dependently inhibited PDGF-mediated MAPK and AKT activation. However, HMC05 did not affect PDGF-mediated HSP27 phosphorylation but it induced HSP27 overexpression and phosphorylation. In addition, medial SMCs in the arterial wall of rats treated with HMC05 showed a significant increase in HSP27 expression compared with that of the control rats.


CONCLUSIONS
HMC05, a strong anti-inflammatory reagent, might use HSP27 as an effector molecule in SMCs to reduce neointimal hyperplasia by inhibiting PDGF-mediated MAPK and AKT activation. HMC05 could be a useful drug candidate for the prevention of restenosis after balloon injury of the arteries.
Lee
Jo Woon Yi
JW
Division of Cardiology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Lee
Bok-Soo
BS
Lee
Ji Yeun
JY
Ku
Hyo Jung
HJ
Jeon
So-Ra
SR
Kim
Joo Yun
JY
Ban
Ji Min
JM
Sung
Sang Hyun
SH
Shin
Heung Mook
HM
Park
Jeong Euy
JE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000077214:Becaplermin; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000473:pathology; D002404:Catheterization; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000517:prevention & control*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000517:prevention & control; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D015398:Signal Transduction
D000893:Anti-Inflammatory Agents; C526235:HMCO5 herbal extract; D055551:HSP27 Heat-Shock Proteins; C486114:Hspb1 protein, rat; D010936:Plant Extracts; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin