Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA.
BACKGROUND
FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI).


RESULTS
We demonstrated an upregulation of sFRP-1 and distinct wnt and fz member expression after MI. We established transgenic (Tg) mice that overexpress FrzA under a cytomegalovirus promoter and developed a model of MI by coronary artery ligation. FrzA reduced cardiac rupture after MI in Tg (6.5% versus 26.4% in controls; n=165, P<0.01). MI was smaller in Tg at each time point (18+/-10.8% of left ventricular circumference versus 30+/-14.2% in controls at day 30; P<0.001). Similar results were found in cryolesion-induced MI. Cardiac function was improved in Tg mice (3800+/-370 mm Hg/s dP/dtmax versus 2800+/-840 in controls; -2800+/-440 dP/dtmin versus -1800+/-211 in controls at day 15; P<0.001). Early leukocyte infiltration had decreased in Tg mice during the first week. Apoptotic index was decreased by 50% in Tg mice at day 7. Matrix metalloproteinase-2 and -9 activity was reduced in Tg mice at day 4, and collagen deposition in the scar was increased in Tg mice. Capillary density in the scar was higher in Tg mice (290+/-103 vessels/mm2 versus 104+/-43 in controls at day 15; P<0.001). Vessels were more muscularized, and mean lumen area was 3-fold higher in Tg animals.


CONCLUSIONS
Overexpression of FrzA, through direct or indirect interaction with different phases of infarct healing, reduced infarct size and improved cardiac function.
Department of Cardiovascular Surgery and Cardiology, Hôpital Haut Lévêque, Pessac, France.
Laurent
L
Barandon
Thierry
T
Couffinhal
Jérome
J
Ezan
Pascale
P
Dufourcq
Pierre
P
Costet
Philippe
P
Alzieu
Lionel
L
Leroux
Catherine
C
Moreau
Danièle
D
Dare
Cécile
C
Duplàa
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002452:Cell Count; D002455:Cell Division / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D051157:Frizzled Receptors; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006342:Heart Rupture, Post-Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007962:Leukocytes / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D003094:Collagen; D003598:Cytoskeletal Proteins; D051157:Frizzled Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D045726:Metalloproteases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C495267:CTNNB1 protein, mouse; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins