Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens.
Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary artery (IMA), however, is much lower than in nearly all other arteries. The etiology of this IMA disease resistance is not well understood. Here, using paired primary IMA and coronary artery SMCs, serum stimulation, siRNA knockdowns, and verifications in porcine vessels in vivo, we investigate the molecular mechanisms that could account for this increased disease resistance of internal mammary SMCs. We show that the residue-specific phosphorylation profile of the retinoblastoma tumor suppressor protein (Rb) appears to differ significantly between IMA and coronary artery SMCs in cultured human cells. We also report that the differential profile of Rb phosphorylation may follow as a consequence of differences in the content of cyclin-dependent kinase 2 (CDK2) and the CDK4 phosphorylation inhibitor p15. Finally, we present evidence that siRNA-mediated CDK2 knockdown alters the profile of Rb phosphorylation in coronary artery SMCs, as well as the proliferative response of these cells to mitogenic stimulation. The intrinsic functional and protein composition specificity of the SMCs population in the coronary artery may contribute to the increased prevalence of restenosis and atherosclerosis in the coronary arteries as compared with the internal mammary arteries.
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
Martin
M
Lange
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
Tatsuya
T
Fujikawa
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
Anna
A
Koulova
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
Sona
S
Kang
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
Michael J
MJ
Griffin
Division of Cardiothoracic Surgery; Alpert Medical School of Brown University; Providence, RI USA.
Antonio D
AD
Lassaletta
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA; Eidgenössisches Departement des Innern EDI Bundesamt für Gesundheit BAG Direktionsbereich Öffentliche Gesundheit; Bern, Switzerland.
Anna
A
Erat
Department of Natural Sciences; University of Applied Sciences Bonn-Rhein-Sieg; Rheinbach, Germany.
Edda
E
Tobiasch
Division of Cardiothoracic Surgery; Alpert Medical School of Brown University; Providence, RI USA.
Cesario
C
Bianchi
Division of Cardiothoracic Surgery; Alpert Medical School of Brown University; Providence, RI USA.
Nassrene
N
Elmadhun
Division of Cardiothoracic Surgery; Alpert Medical School of Brown University; Providence, RI USA.
Frank W
FW
Sellke
Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
Anny
A
Usheva
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D016895:Culture Media, Serum-Free; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000166:cytology / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D016160:Retinoblastoma Protein / Q000378:metabolism*; D044967:Serum; D013552:Swine; D050986:YY1 Transcription Factor / Q000378:metabolism
D016895:Culture Media, Serum-Free; D050762:Cyclin-Dependent Kinase Inhibitor p15; D008934:Mitogens; D016160:Retinoblastoma Protein; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4
CDK2; cell migration; cell proliferation; coronary artery; internal mammary artery; retinoblastoma protein phosphorylation; smooth muscle cells