Diabetes mellitus downregulates expression of connexin43 in rat aortic medial smooth muscle cells and can be reversed by simvastatin and losartan therapy.
BACKGROUND
Diabetes mellitus (DM) plays a crucial role in the pathogenesis of initiation and propagation of atherosclerosis. Although previous studies have suggested that interactions between cells form the framework for understanding the pathogenesis of atherosclerosis, little is known about how DM impacts intercellular communication within arteries, which occurs via connexin43 (Cx43) gap junctions (GJs). This study tested the hypothesis that DM suppresses expression of Cx43 GJs, and that this suppression can be abrogated via simvastatin or losartan treatment.


METHODS
An experimental model of DM (induced by streptozocin 60 mg/kg body weight) in adult male rats (n = 24) was utilized to investigate Cx43 expression in the aorta. These rats were divided into group I (insulin therapy only), group II (insulin plus simvastatin 20 mg/kg/day) and group III (insulin plus losartan 20 mg/kg/day). Twenty-four diabetic rats and 8 healthy rats (group IV) were sacrificed 3 weeks after DM induction for Western blot and immunofluorescence analysis.


RESULTS
By day 21, the blood sugar level was significantly higher than the respective baseline values in groups I, II and III (all values of p < 0.0001). Additionally, the final blood sugar levels of groups I-III were significantly higher than that of group IV (p < 0.0001). The final body weight in group IV was significantly higher than that in groups I-III (all values of p < 0.0001). Experimental results demonstrated that Cx43 expression in the aortic wall did not differ among groups II-IV (p > 0.1). However, compared with groups II-IV, Cx43 expression in the aortic wall was significantly mitigated in group I (all values of p < 0.05). Western blot results showed that relative density of Cx43 to beta-actin was significantly higher in groups II-IV than in group I (p < 0.01).


CONCLUSIONS
DM markedly suppressed expression of Cx43 in rat aortic walls. Both simvastatin and losartan treatment significantly reversed the effects of DM on integrity of Cx43 expression.
Sheu
Jiunn-Jye
JJ
Department of Cardiovascular Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C.
Tsai
Tzu-Hsien
TH
Chang
Li-Teh
LT
Chiang
Chiang-Hua
CH
Youssef
Ali A
AA
Sun
Cheuk-Kwan
CK
Chang
Nyuk-Kong
NK
Yip
Hon-Kan
HK
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D018031:Connexin 43 / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D018031:Connexin 43; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D019808:Losartan