Losartan reduced connexin43 expression in left ventricular myocardium of spontaneously hypertensive rats.
OBJECTIVE
To assess the effect of angiotensin II type 1 (AT(1)) receptor antagonist losartan on myocardium connexin43 (Cx43) gap junction (GJ) expression in spontaneously hypertensive rats (SHRs) and investigate possible mechanisms.


METHODS
Sixteen 9-week-old male SHRs and 8 age-matched male Wistar-Kyoto (WKY) rats were included in this study. SHRs were randomly divided into two groups to receive losartan at 30 mg/(kg x d) by oral gavage once daily for 8 weeks (SHR-L) or vehicle (0.9% saline) to act as controls (SHR-V); WKY rats receiving vehicle for 8 weeks served as normotensive controls. At the end of the experiment, rats were sacrificed and the hearts were removed. Expressions of Cx43 and nuclear factor-kappaB p65 (NF-kappaB p65) proteins in all three groups were observed and further investigations on the effect of angiotensin II type 1 receptor antagonist losartan (30 mg/(kg x d), 8 weeks) on Cx43 expression were conducted with Western blot and immunohistochemistry. NF-kappaB p65 protein in nuclear extracts was determined by Western blot.


RESULTS
Left ventricular (LV) hypertrophy was prominent in SHRs, Cx43 and NF-kappaB p65 protein expressions were obviously upregulated and Cx43 distribution was dispersed over the cell surface. Treatment with losarton reduced the over-expressions of Cx43 and NF-kappaB p65 in LV myocardium. The distribution of Cx43 gap junction also became much regular and confined to intercalated disk after losartan treatment.


CONCLUSIONS
Cx43 level was upregulated in LV myocardium of SHR during early stage of hypertrophy. Angiotensin II type 1 receptor antagonist losartan prevented Cx43 gap junction remodeling in hypertrophied left ventricles, possibly through the NF-kappaB pathway.
Zhao
Li-li
LL
Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Chen
Hong-juan
HJ
Chen
Jun-zhu
JZ
Yu
Min
M
Ni
Yun-lan
YL
Zhang
Wei-fang
WF
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D018031:Connexin 43 / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D051996:Transcription Factor RelA / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D018031:Connexin 43; C498145:Rela protein, rat; D051996:Transcription Factor RelA; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain; D019808:Losartan