Activation of Protein Kinase G (PKG) Reduces Neointimal Hyperplasia, Inhibits Platelet Aggregation, and Facilitates Re-endothelialization.
In spite of its great success in reducing restenosis, drug-eluting stent (DES) has unfavorable aspects such as stent thrombosis and delayed re-endothelialization. We examined the effects of PKG activation by Exisulind on neointimal formation, platelet aggregation, and re-endothelialization. Exisulind significantly reduced VSMCs viability, cell cycle progression, migration, and neointimal hyperplasia after vascular injury in rat carotid arteries. Interestingly, in contrast to the effect on VSMC viability, Exisulind did not reduce the viability of endothelial cells. Increased PKG activity by Exisulind inhibited PDGF-stimulated phenotype change of VSMCs from a contractile to a synthetic form. Conversely, the use of PKG inhibitor or gene transfer of dominant-negative PKG reversed the effects of Exisulind, resulting in the increased viability of VSMCs and neointimal formation. In addition, Exisulind facilitated the differentiation of peripheral blood mononuclear cells to endothelial lineage via PKG pathway, while inhibiting to VSMCs lineage, which was correlated with the enhanced re-endothelialization in vivo. Finally, Exisulind reduced platelet aggregation, which was mediated via PKG activation. This study demonstrated that Exisulind inhibits neointimal formation and platelet aggregation while increasing re-endothelialization via PKG pathway. These findings suggest that Exisulind could be a promising candidate drug of DES for the prevention of restenosis without other complications.
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
Ju-Young
JY
Kim
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Han-Mo
HM
Yang
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
Joo-Eun
JE
Lee
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
Baek-Kyung
BK
Kim
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
Sooryeonhwa
S
Jin
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
Jaewon
J
Lee
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Kyung-Woo
KW
Park
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Hyun-Jai
HJ
Cho
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
Yoo-Wook
YW
Kwon
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Hae-Young
HY
Lee
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Hyun-Jae
HJ
Kang
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Byung-Hee
BH
Oh
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Young-Bae
YB
Park
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.|Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
Hyo-Soo
HS
Kim
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation
D010982:Platelet-Derived Growth Factor; D013467:Sulindac; D017869:Cyclic GMP-Dependent Protein Kinases; C025463:sulindac sulfone