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. 2008 Jun;9(6):448-54.
doi: 10.1631/jzus.B0820050.

Losartan reduced connexin43 expression in left ventricular myocardium of spontaneously hypertensive rats

Li-li Zhao  1 , Hong-juan Chen, Jun-zhu Chen, Min Yu, Yun-lan Ni, Wei-fang Zhang
Affiliations

Losartan reduced connexin43 expression in left ventricular myocardium of spontaneously hypertensive rats

Li-li Zhao et al. J Zhejiang Univ Sci B. 2008 Jun.

Abstract

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.

Conclusion: 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.

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Figures

Fig. 1
Fig. 1
Pathological changes of left ventricular cardiocytes in three groups (HE stain). (a) In WKY-V group, cardiocytes with normal size were regular; (b) In SHR-V group, the increased sizes of cardiocytes and myofiber disarray were prominent; (c) In SHR-L group, ventricular cardiocytes with decreased size after treatment with 30 mg/(kg·d) losartan were more regular than those in untreated group
Fig. 1
Fig. 1
Pathological changes of left ventricular cardiocytes in three groups (HE stain). (a) In WKY-V group, cardiocytes with normal size were regular; (b) In SHR-V group, the increased sizes of cardiocytes and myofiber disarray were prominent; (c) In SHR-L group, ventricular cardiocytes with decreased size after treatment with 30 mg/(kg·d) losartan were more regular than those in untreated group
Fig. 1
Fig. 1
Pathological changes of left ventricular cardiocytes in three groups (HE stain). (a) In WKY-V group, cardiocytes with normal size were regular; (b) In SHR-V group, the increased sizes of cardiocytes and myofiber disarray were prominent; (c) In SHR-L group, ventricular cardiocytes with decreased size after treatment with 30 mg/(kg·d) losartan were more regular than those in untreated group
Fig. 2
Fig. 2
Changes of spatial organization of Cx43 in LV myocardium determined by immunohistochemistry. (a) In WKY-V group, the distribution of Cx43 was homogeneous in normal ventricular myocardium; (b) In SHR-V group, the distribution of Cx43 was heterogeneous; (c) In SHR-L group, the distribution of Cx43 was much regular after treatment with 30 mg/(kg·d) losartan
Fig. 2
Fig. 2
Changes of spatial organization of Cx43 in LV myocardium determined by immunohistochemistry. (a) In WKY-V group, the distribution of Cx43 was homogeneous in normal ventricular myocardium; (b) In SHR-V group, the distribution of Cx43 was heterogeneous; (c) In SHR-L group, the distribution of Cx43 was much regular after treatment with 30 mg/(kg·d) losartan
Fig. 2
Fig. 2
Changes of spatial organization of Cx43 in LV myocardium determined by immunohistochemistry. (a) In WKY-V group, the distribution of Cx43 was homogeneous in normal ventricular myocardium; (b) In SHR-V group, the distribution of Cx43 was heterogeneous; (c) In SHR-L group, the distribution of Cx43 was much regular after treatment with 30 mg/(kg·d) losartan
Fig. 3
Fig. 3
Western blot analysis of Cx43 and NF-κB p65 in three groups. (a) Representative Cx43 immunoblot (upper panel) and relative Cx43 protein levels (lower panel, mean±SD); (b) Representative NF-κB p65 immunoblot (upper panel) and relative NF-κB p65 protein levels (lower panel, mean±SD) * P<0.05 vs WKY-V group, # P<0.05 vs SHR-V group; ** P<0.001 vs WKY-V group; ## P<0.001 vs SHR-V group
Fig. 3
Fig. 3
Western blot analysis of Cx43 and NF-κB p65 in three groups. (a) Representative Cx43 immunoblot (upper panel) and relative Cx43 protein levels (lower panel, mean±SD); (b) Representative NF-κB p65 immunoblot (upper panel) and relative NF-κB p65 protein levels (lower panel, mean±SD) * P<0.05 vs WKY-V group, # P<0.05 vs SHR-V group; ** P<0.001 vs WKY-V group; ## P<0.001 vs SHR-V group
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