TY - JOUR
T1 - PARP1 is required for adhesion molecule expression in atherogenesis
AU - Von Lukowicz, Tobias
AU - Hassa, Paul O.
AU - Lohmann, Christine
AU - Borén, Jan
AU - Braunersreuther, Vincent
AU - Mach, François
AU - Odermatt, Bernhard
AU - Gersbach, Monika
AU - Camici, Giovanni G.
AU - Stähli, Barbara E.
AU - Tanner, Felix C.
AU - Hottiger, Michael O.
AU - Lüscher, Thomas F.
AU - Matter, Christian M.
N1 - Funding Information:
This work was funded in part by grants from the European Union G5RD-CT-2001-00532 and Bundesamt für Bildung und Wissenschaft 02.0057 (CMM, TFL), the Swiss National Science Foundation 31-114094/1 (CMM), 3100-068118 (TFL, CMM), and 31-109315.05 (MOH, POH), the University Research Priority Program ‘Integrative Human Physiology’ at the University of Zurich (CMM, TvL, TFL), the Novartis Research Foundation (CMM), and the Kanton of Zurich, Switzerland (MOH, POH).
PY - 2008/4
Y1 - 2008/4
N2 - Aims: Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases. Methods and results: In order to test the role of PARP in atherogenesis, we applied chronic pharmacological PARP inhibition or genetic PARP1 deletion in atherosclerosis-prone apolipoprotein E-deficient mice and measured plaque formation, adhesion molecules, and features of plaque vulnerability. After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E-deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51%, respectively (P < 0.05, n ≥ 9). PARP inhibition or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase, vascular cell adhesion molecule-1, and P- and E-selectin. Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death (P < 0.05, n ≥ 6). Conclusion: Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis.
AB - Aims: Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases. Methods and results: In order to test the role of PARP in atherogenesis, we applied chronic pharmacological PARP inhibition or genetic PARP1 deletion in atherosclerosis-prone apolipoprotein E-deficient mice and measured plaque formation, adhesion molecules, and features of plaque vulnerability. After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E-deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51%, respectively (P < 0.05, n ≥ 9). PARP inhibition or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase, vascular cell adhesion molecule-1, and P- and E-selectin. Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death (P < 0.05, n ≥ 6). Conclusion: Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis.
KW - Adhesion molecule
KW - Atherosclerosis
KW - Inflammation
KW - Macrophages
KW - PARP
UR - http://www.scopus.com/inward/record.url?scp=41149096487&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvm110
DO - 10.1093/cvr/cvm110
M3 - Article
C2 - 18093987
AN - SCOPUS:41149096487
SN - 0008-6363
VL - 78
SP - 158
EP - 166
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -