Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure.
Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1beta was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.
Cheng
Xian Wu
XW
Department of Cardiovascular Genome Science, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. xianwu@med.nagoya-u.ac.jp
Obata
Koji
K
Kuzuya
Masafumi
M
Izawa
Hideo
H
Nakamura
Kae
K
Asai
Eri
E
Nagasaka
Tetsuro
T
Saka
Masako
M
Kimata
Takahiro
T
Noda
Akiko
A
Nagata
Kohzo
K
Jin
Hai
H
Shi
Guo-Ping
GP
Iguchi
Akihisa
A
Murohara
Toyoaki
T
Yokota
Mitsuhiro
M
D000328:Adult; D000368:Aged; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology; D002403:Cathepsins / Q000096:biosynthesis* / Q000378:metabolism; D004549:Elastin / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D006973:Hypertension / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D020303:Rats, Inbred Dahl; D015854:Up-Regulation / Q000502:physiology*
D004549:Elastin; D002403:Cathepsins