Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model.



Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent.



Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS.
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Stijntje
S
Hibender
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Romy
R
Franken
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Cindy
C
van Roomen
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Anique
A
Ter Braake
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Ingeborg
I
van der Made
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Edith E
EE
Schermer
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Quinn
Q
Gunst
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Maurice J
MJ
van den Hoff
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Esther
E
Lutgens
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Yigal M
YM
Pinto
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Maarten
M
Groenink
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Aeilko H
AH
Zwinderman
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Barbara J M
BJ
Mulder
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.).
Carlie J M
CJ
de Vries
From the Department of Medical Biochemistry (S.H., C.v.R., A.t.B., E.E.S., E.L., C.J.M.d.V., V.d.W.), Department of Cardiology (R.F., M.G., B.J.M.M.), Department of Experimental Cardiology (I.v.d.M., Y.M.P.), Heart Failure Research Center (Q.G., M.J.v.d.H.), Department of Radiology (M.G.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; and Institute for Cardiovascular Prevention (IPEK) and Ludwig Maximilians University, Munich, Germany (E.L.). v.dewaard@amc.uva.nl.
Vivian
V
de Waard
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D054392:Adipokines
D004549:Elastin; D000071838:Fibrillin-1; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D000077185:Resveratrol; D056564:Sirtuin 1; D013267:Stilbenes; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C547014:MIRN29 microRNA, mouse; C052617:Bcl2 protein, mouse; C470545:Sirt1 protein, mouse
Marfan syndrome; aortic aneurysm; extracellular matrix; micro-RNAs; resveratrol; sirtuin-1