[Association between lysosomal cysteine protease cathepsin's activation and left ventricular function and remodeling in hypertensive heart failure rats].
OBJECTIVE
To observe myocardial cathepsin (Cat) S expression and activity in hypertensive heart failure rats.


METHODS
The expression and activity of Cat S were determined in the left ventricular (LV) myocardium (LVM) of Dahl salt-sensitive rats fed either a high-salt (HS, 8%) or low-salt (LS, 0, 3%, controls) diet starting at age 7 weeks for 12 weeks (hypertrophy model, H-LVH) or 19 weeks (heart failure model, H-HF). Age-matched rats served as controls and human normal, hypertensive and heart failure myocardial specimen were also examined for changes on the expression and activity of Cat S.


RESULTS
Reverse transcription and real-time polymerase chain reaction analysis revealed significantly upregulated Cat S mRNA in rats with H-HF than in rats with H-LVH or in control rats and Cat S mRNA expression is negatively correlated with LVEF (r = -0.88, P < 0.05). In situ and immunohistochemistry examinations showed that Cat S was localized predominantly in cardiac myocytes (CMCs) and coronary vascular smooth muscle cells (SMC). Elastic lamina fragmentations and Cat S-dependent elastolytic activity were significantly increased in H-HF-rats. The expression of interleukin-1 beta was also increased in the LVM of H-HF rats, and this cytokine was found to increase the Cat S protein expression in culture neonatal CMCs. Similar results were revealed in human myocardial specimens.


CONCLUSIONS
Elastolytic Cat S might play an important role in the pathogenesis of myocardial remodeling and heart failure and Cat S might serve as a novel therapeutic target in preventing or reversing hypertension induced LV remodeling and heart failure.
Cheng
Xian-Wu
XW
Department of Cardiovascular Research Medicine, Nagoya University School of Medicine, Aichiken, Nagoya 466-8550, Japan. xianwu@med.nagoya-u.ac.jp
Zhang
Jie
J
Song
Hui
H
Yang
Guang
G
Qin
Xiao-Zhi
XZ
Guan
Li-Ke
LK
Jin
Hai
H
Okumura
Kenji
K
Murohara
Toyoaki
T
D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002403:Cathepsins / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D020303:Rats, Inbred Dahl; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D002403:Cathepsins; C028217:cathepsin S