Expression and tissue localization of beta-catenin, alpha-actinin and chondroitin sulfate proteoglycan 6 is modulated during rat and human left ventricular hypertrophy.
Left ventricular hypertrophy (LVH) correlates with chronic renal failure and is one of the most important causes of cardiac mortality. The understanding of the molecular complexity of the disease will help to find biomarkers that open new perspectives about early diagnosis and therapy. This work describes the identification of mediators during pathogenesis relevant for structural remodeling processes of cardiac tissue in uremic LVH. An established rat model of chronic renal failure allowed whole-genome transcriptome analyses as well as the investigation of differential expressed proteins in uremic LVH. The localization of potential biomarkers encoded by candidate genes was done by immunohistochemical analyses of cardiac tissue of the animal model as well as cardiac sections of LVH diseased patients. In addition, the induction of human cardiac fibroblasts (HCF) and human umbilical vein endothelial cells (HUVEC) with the LVH mediator angiotensin II enabled us to investigate uremic LVH progression in vitro. These results point to alterations of myocardial intercellular and cell-matrix contacts in hypertrophic cardiac tissue. Obviously, structural changes of the extracellular matrix are significantly modulated by beta-catenin associated signaling pathways. Interestingly, intracellular translocation of beta-catenin, alpha-actinin and chondroitin sulfate proteoglycan 6 (CSPG6/SMC3) was observed in the animal model and in LVH patients. Our results show that the parallel investigation of rat and human cardiac tissue as well as human cellular models in vitro represents a promising strategy to identify reliable biomarkers of LVH.
Ridinger
Heidrun
H
RZPD German Resource Center for Genome Research, 69120 Heidelberg, Germany.
Rutenberg
Christiane
C
Lutz
Diana
D
Buness
Andreas
A
Petersen
Iver
I
Amann
Kerstin
K
Maercker
Christian
C
D000185:Actinin / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015676:Osteonectin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000502:physiology; D053675:Versicans / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D015676:Osteonectin; C492318:SMC3 protein, human; C492316:SMC3 protein, rat; C508324:Vcan protein, rat; D051176:beta Catenin; D000185:Actinin; D000804:Angiotensin II; D053675:Versicans; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2