A newly developed angiotensin II type 1 receptor antagonist, CS866, promotes regression of cardiac hypertrophy by reducing integrin beta1 expression.
Previous studies have demonstrated that integrins link the extracellular matrix to the hypertrophic response pathway of cardiac myocytes in vitro. To examine the direct relation between integrin beta1 and cardiac hypertrophy in vivo, we studied the effects of a newly developed angiotensin II type 1 (AT1) blocker, CS866 (ARB; 10 mg/kg/day), an angiotensin-converting enzyme inhibitor, temocapril (ACEI, 10 mg/kg/day), or both on modulation of integrin beta1 in the hypertrophied hearts of stroke-prone spontaneously hypertensive rats (SHRSP) 6 to 12 weeks of age. Treatments with ARB, ACEI, and combination therapy significantly reduced systolic blood pressure. However, the reduction in cardiac hypertrophy was greater in SHRSP treated with ARB or combination therapy than in those treated with ACEI. Multiplex reverse transcription-polymerase chain reaction revealed significantly higher mRNA expression of atrial natriuretic factor, AT1 receptor, and integrin beta1 in untreated SHRSP than in normotensive Wistar-Kyoto rats (WKY). The mRNA levels of ANP, AT1 receptor, and integrin B1 in SHRSP were significantly decreased by treatment with ARB, ACEI, or combination therapy. Decreased mRNA expression of ANP, AT1 receptor, and integrin beta1 in the treated SHRSP was associated with reductions in blood pressure; ARB and combination therapy produced greater decreases in expression than did ACEI. These observations suggest that CS866 has a beneficial effect on myocyte hypertrophy and that down-regulation of AT1 receptor and suppression of integrin beta1 participate in the regression of pressure-induced cardiac hypertrophy in vivo. The correlation between the expression of integrin beta1 and AT1 receptor was significant. Our results also suggest that integrin expression by myocytes might be modulated by angiotensin II via AT1 receptor.
Jia
Nan
N
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Okamoto
Hiroshi
H
Shimizu
Toshihiro
T
Chiba
Satoru
S
Matsui
Yutaka
Y
Sugawara
Takeshi
T
Akino
Masatoshi
M
Kitabatake
Akira
A
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000494:pharmacology*; D019012:Integrin beta1 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D000068557:Olmesartan Medoxomil; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D019012:Integrin beta1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013841:Thiazepines; D000068557:Olmesartan Medoxomil; D009320:Atrial Natriuretic Factor; C055603:temocapril hydrochloride