Carboxyl terminus of heat shock protein 70-interacting protein inhibits angiotensin II-induced cardiac remodeling.
BACKGROUND
The carboxyl terminus of heat shock protein 70-interacting protein (CHIP), an E3 ligase/chaperone, was found to protect cardiomyocytes against apoptosis induced by ischemic injury; however, the functional role of CHIP in remodeling induced by angiotensin II (Ang II) remains unclear.


METHODS
We generated CHIP-overexpressed transgenic (TG) mice infused with Ang II (1,500 ng/kg/min) or saline for days or small interfering RNA (siRNA) knockdown of neonatal rat cardiomyocytes. Heart sections were stained with hematoxylin and eosin, Masson trichrome, TdT-mediated dUTP nick-end labeling (TUNEL) staining, and immunohistochemistry, and the levels of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) were measured by western blot analysis.


RESULTS
Seven days after Ang II infusion, cardiac-specific overexpression of CHIP significantly enhanced cardiac contractile performance in mice and attenuated cardiac apoptosis, fibrosis, and inflammation: the number of TUNEL-positive cells, fibrotic areas, macrophage infiltration, and the expression of interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) in heart tissues were decreased as compared with wild-type (WT) mice (all P < 0.05). In contrast, CHIP siRNA knockdown markedly increased Ang II-induced apoptosis and the expression of proinflammatory cytokines, as compared with siRNA control. The mechanisms underlying these beneficial actions were associated with CHIP-mediated inhibition of NF-κB and MAPK (p38 and JNK) pathways.


CONCLUSIONS
CHIP plays an important role in regulating Ang II-triggered hypertensive cardiac apoptosis, inflammation, and fibrosis.
Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Kun
K
Yang
Tian-Peng
TP
Zhang
Cui
C
Tian
Li-Xin
LX
Jia
Jie
J
Du
Hui-Hua
HH
Li
D000804:Angiotensin II / Q000187:drug effects*; D000809:Angiotensins / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology
D000809:Angiotensins; D016328:NF-kappa B; D000804:Angiotensin II; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020928:Mitogen-Activated Protein Kinases