Signal pathways involved in reverse remodeling of the hypertrophic rat heart after pressure unloading.
BACKGROUND
The purpose of this study was to gain a better understanding of molecular changes associated with the beneficial reverse remodeling through heterotopic transplantation model of rat hypertrophic hearts.


METHODS
Stable cardiac hypertrophy was induced by abdominal aortic constriction (AAC) in Lewis rats (6 weeks). Left ventricular (LV) pressure unloading was induced by heterotopic transplantation of hypertrophic hearts (AAC-HT) (2 weeks). We measured heart weight (HW), LV weight (LVW) and the LV-to-final body weight ratio (LVW/BW). Cross-sectional areas of cardiomyocyte and collagen content were assessed by hematoxylin/eosin staining and picrosirius red staining, respectively. We further analyzed the signaling pathways of mitogen-activated protein kinases (MAPKs), Akt/GSK3β, NF-κB, metalloproteinase-2,9 (MMP-2, 9) and tissue inhibitors of metalloproteinase-1 (TIMP-1) by Western blot.


RESULTS
The HW, LVW and LVW/BW in AAC hearts were higher than normal hearts, but the transplanted hearts showed a significant reduction in HW, LVW and LVW/BW compared to AAC hearts. Unloading induced a decrease in cardiomyocyte size and an increase in collagen content in AAC-HT hearts. A significant decrease in phosphorylation of p44/p42 MAP kinases (ERK), Akt, GSK3β and NF-κB was detected in AAC-HT hearts, but the phosphorylation of p38 MAP kinase and Jun-N-terminal kinase (JNK) was not changed. MMP-2, MMP-9 and TIMP-1 activity also increased accompanied by unloading.


CONCLUSIONS
Pressure unloading of the hypertrophic heart caused a reverse remodeling through regulating the ERK, Akt/GSK3β, and NFκB signal pathways, revealing these as potential target pathways for reversal of LV hypertrophy.
Xu
Ruixia
R
Research Center for Cardiovascular Regenerative Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing 100037, China.
Lin
Fuqiang
F
Zhang
Shiju
S
Chen
Xi
X
Hu
Shengshou
S
Zheng
Zhe
Z
D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
D016328:NF-kappa B; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9