Effects Of Enalapril, Irebesartan And Angiotensin-(1-7) On The Atrial Structural Remodeling And RAS In Atrial Tachypacing Dogs

Objective:To observe the atrial structural remodeling and the expression of angiotensin converting enzyme (ACE), ACE2, angiotensin II receptor subtypes (AT1R and AT2R), extracellular signal-regulated kinase (ERK), phosphorylated ERK (P-ERK) and Mas receptor in a atrial tachypacing model of dogs, and to investigate the effects of enalapril, irbesartan and angiotensin-(1-7) [Ang-(1-7)] on the atrial tachypacing-induced cardiac structural remodeling and renin-angiotensin system activation.Methods:30 mature mongrel dogs were assigned to the sham-operated group (S), pacing-control group (C), pacing and enalapril-treated group (EN), pacing and irbesartan-treated group (IB) or pacing and Ang-(1-7)-treated group (A),6 dogs in each group. A programmable pacemaker was inserted in a subcutaneous pocker, and an atrial pacing lead was positioned in the right atrium through right jugular vein. The rapid atrial pacing at 500 beats per minute was maintained for 2 weeks except sham group. The dogs in the EN, IB and A groups respectively received enalapril (2mg·Kg-1·d-1), irbesartan (60mg·Kg-1·d-1) orally or Ang-(1-7) (6μg·Kg-1·h-1) intravenously via mini-osmotic pumps during the pacing period. RT-PCR was applied to assess the mRNA expression of ACE2 and AT1R in right atrial tissue. Hematoxylin-Eosin staining was used to observe the histopatholagic changes in each group, and immunohistochemical staining to evaluate the protein expression of ACE, ACE2, AT1R, AT2R, ERK, P-ERK and Mas in right atrial local tissue. Western Blot was performed to estimate the ERK1/ERK2 protein expression.Result:1. RT-PCR:In the pacing-control group, ACE2 mRNA expression was declined and AT1R expression was markedly elevated than sham group (P<0.05). Enalapril, irbesartan or angiotensin-(1-7) treatement caused increased ACE2 mRNA expression and decreased AT1R expression in comparison with the pacing-control group (P<0.05).2. Hematoxylin-Eosin staining:In the pacing-control group, the heterogeneity in the size and arrangement of atrial myocytes was found, as well as the adipose tissue infiltration and interstitial fibrosis hyperthophy. While these pathological abnormal findings were attenuated in the enapapril, irbesartan and angiotensin-(1-7)-treated groups.3. Immunohistochemical staining:Compared with the sham group, the protein levels of ACE, AT1R, AT2R, ERK, P-ERK and Mas in pacing-control group were significantly increased (P<0.05 or P<0.001). Enapapril, irbesartan and angiotensin-(1-7) significantly inhibited the overexpression of ERK, P-ERK and Mas (P<0.05 or P<0.001 vs pacing-control group). ACE and AT1R protein expression were significantly downregulated in irbesartan and angiotensin-(1-7)-treated groups (P<0.05 or P<0.001 vs pacing-control group). AT2R protein level in angiotensin-(1-7)-treated group was markedly decreased than pacing-control group (P<0.05). ACE2 protein level was significantly reduced in pacing-control group (P<0.05), and enapapril, irbesartan and angiotensin-(1-7) upregulated the ACE2 expression (P<0.05 vs pacing-control group).4. Western Blot: ERK1/ERK2 protein levels were markedly increased in pacing-control group than sham group (P<0.05). Enapapril, irbesartan and angiotensin-(1-7) significantly downregulated ERK1/ERK2 protein expression (P<0.05 vs pacing-control group).Conclusion:Chronic atrial tachypacing leads to atrial structural remodeling and renin-angiotensin system activaton, which is contribute to the vulnerability of atrial fibrillation. Enalapril, irbesartan and angiotensin-(1-7) can attenuate the atrial tachypacing-induced cardiac structural remodeling and suppress the activation of RAS and AngⅡ-mediated ERK signal pathway, thereby inhibiting the development of atrial fibrillation substrate.