RGD Reference Report - Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis. - Rat Genome Database

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Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis.

Authors: Kaschina, E  Stoll, M  Sommerfeld, M  Steckelings, UM  Kreutz, R  Unger, T 
Citation: Kaschina E, etal., Physiol Genomics 2004 Sep 16;19(1):41-9. Epub 2004 Jul 06.
RGD ID: 1302825
Pubmed: PMID:15238617   (View Abstract at PubMed)
DOI: DOI:10.1152/physiolgenomics.00035.2004   (Journal Full-text)

Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BNRatabdominal aortic aneurysm inducedIAGPcontrolled cholesterol content diet or controlled fat content diet RGD 
BN/KaRatabdominal aortic aneurysm inducedIAGPcontrolled cholesterol content diet or controlled fat content diet RGD 
CASP3Humanabdominal aortic aneurysm  ISOCasp3 (Rattus norvegicus)protein:increased expression:aorta (rat)RGD 
CSF2Humanabdominal aortic aneurysm  ISOCsf2 (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
Casp3Ratabdominal aortic aneurysm  IEP protein:increased expression:aorta (rat)RGD 
Casp3Mouseabdominal aortic aneurysm  ISOCasp3 (Rattus norvegicus)protein:increased expression:aorta (rat)RGD 
Csf2Ratabdominal aortic aneurysm  IEP protein:decreased expression:serum (rat)RGD 
Csf2Mouseabdominal aortic aneurysm  ISOCsf2 (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
FASLGHumanabdominal aortic aneurysm  ISOFaslg (Rattus norvegicus)protein:increased expression:aorta (rat)RGD 
FaslMouseabdominal aortic aneurysm  ISOFaslg (Rattus norvegicus)protein:increased expression:aorta (rat)RGD 
FaslgRatabdominal aortic aneurysm  IEP protein:increased expression:aorta (rat)RGD 
IFNGHumanabdominal aortic aneurysm  ISOIfng (Rattus norvegicus)protein:increased expression:serum (rat)RGD 
IL10Humanabdominal aortic aneurysm  ISOIl10 (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
IL1BHumanabdominal aortic aneurysm  ISOIl1b (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
IL4Humanabdominal aortic aneurysm  ISOIl4 (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
IfngRatabdominal aortic aneurysm  IEP protein:increased expression:serum (rat)RGD 
IfngMouseabdominal aortic aneurysm  ISOIfng (Rattus norvegicus)protein:increased expression:serum (rat)RGD 
Il10Ratabdominal aortic aneurysm  IEP protein:decreased expression:serum (rat)RGD 
Il10Mouseabdominal aortic aneurysm  ISOIl10 (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
Il1bRatabdominal aortic aneurysm  IEP protein:decreased expression:serum (rat)RGD 
Il1bMouseabdominal aortic aneurysm  ISOIl1b (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
Il4Mouseabdominal aortic aneurysm  ISOIl4 (Rattus norvegicus)protein:decreased expression:serum (rat)RGD 
Kng1Mouseabdominal aortic aneurysm  ISOKng1 (Rattus norvegicus)DNA:SNP:487G>ARGD 
Kng1Ratabdominal aortic aneurysm  IAGP DNA:SNP:487G>ARGD 
MMP2Humanabdominal aortic aneurysm  ISOMmp2 (Rattus norvegicus) RGD 
MMP3Humanabdominal aortic aneurysm  ISOMmp3 (Rattus norvegicus)protein:increased expression:aorta (rat)RGD 
Mmp2Ratabdominal aortic aneurysm  IEP  RGD 
Mmp2Mouseabdominal aortic aneurysm  ISOMmp2 (Rattus norvegicus) RGD 
Mmp3Ratabdominal aortic aneurysm  IEP protein:increased expression:aorta (rat)RGD 
Mmp3Mouseabdominal aortic aneurysm  ISOMmp3 (Rattus norvegicus)protein:increased expression:aorta (rat)RGD 
TIMP4Humanabdominal aortic aneurysm  ISOTimp4 (Rattus norvegicus)protein:decreased expression:aorta (rat)RGD 
Timp4Ratabdominal aortic aneurysm  IEP protein:decreased expression:aorta (rat)RGD 
Timp4Mouseabdominal aortic aneurysm  ISOTimp4 (Rattus norvegicus)protein:decreased expression:aorta (rat)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BN/KaRatdecreased aorta elastin content  IAGP compared to BNRGD 
BN/KaRatdecreased aorta elastin content inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to BNRGD 
BN/KaRatdecreased circulating HDL cholesterol level  IAGP compared to W and BNRGD 
BN/KaRatdecreased circulating interleukin-1 beta level  IAGP compared to BNRGD 
BN/KaRatdecreased circulating interleukin-1 beta level MODEL: inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to BNRGD 
BN/KaRatdecreased circulating interleukin-10 level  IAGP compared to BNRGD 
BN/KaRatdecreased circulating interleukin-10 level inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to BNRGD 
BN/KaRatdecreased circulating interleukin-4 level  IAGP compared to BNRGD 
BN/KaRatdecreased circulating interleukin-4 level inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to BNRGD 
BN/KaRatdecreased circulating triglyceride level  IAGP compared to W and BNRGD 
BN/KaRatdecreased circulating triglyceride level inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to W RGD 
BN/KaRathepatic steatosis inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to W and BNRGD 
BN/KaRatincreased apoptosis inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to W and BNRGD 
BN/KaRatincreased circulating HDL cholesterol level inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to W and BNRGD 
BN/KaRatincreased circulating interferon-gamma level  IAGP compared to WRGD 
BN/KaRatincreased circulating interferon-gamma level inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to W and BNRGD 
BN/KaRatincreased circulating triglyceride level inducedIAGPcontrolled cholesterol content diet or controlled fat content dietcompared to BNRGD 
Objects Annotated

Genes (Rattus norvegicus)
Casp3  (caspase 3)
Csf2  (colony stimulating factor 2)
Faslg  (Fas ligand)
Ifng  (interferon gamma)
Il10  (interleukin 10)
Il1b  (interleukin 1 beta)
Kng1  (kininogen 1)
Mmp2  (matrix metallopeptidase 2)
Mmp3  (matrix metallopeptidase 3)
Timp4  (TIMP metallopeptidase inhibitor 4)

Genes (Mus musculus)
Casp3  (caspase 3)
Csf2  (colony stimulating factor 2 (granulocyte-macrophage))
Fasl  (Fas ligand)
Ifng  (interferon gamma)
Il10  (interleukin 10)
Il1b  (interleukin 1 beta)
Il4  (interleukin 4)
Kng1  (kininogen 1)
Mmp2  (matrix metallopeptidase 2)
Mmp3  (matrix metallopeptidase 3)
Timp4  (tissue inhibitor of metalloproteinase 4)

Genes (Homo sapiens)
CASP3  (caspase 3)
CSF2  (colony stimulating factor 2)
FASLG  (Fas ligand)
IFNG  (interferon gamma)
IL10  (interleukin 10)
IL1B  (interleukin 1 beta)
IL4  (interleukin 4)
MMP2  (matrix metallopeptidase 2)
MMP3  (matrix metallopeptidase 3)
TIMP4  (TIMP metallopeptidase inhibitor 4)

Strains
BN  (BN)
BN/Ka  (Brown Norway Katholiek (kininogen or kinin deficient))


Additional Information