Cavopulmonary anastomosis induces pulmonary expression of the angiotensin II receptor family.
BACKGROUND
Cavopulmonary anastomosis is used for palliation of cyanotic cardiac lesions. Postoperative development of pulmonary arteriovenous malformations can be significant in 10% to 25% of patients. To study the basis for formation of arteriovenous malformations, we developed an ovine model that reliably induces their development 8 weeks after cavopulmonary anastomosis. Previously, we found that cavopulmonary anastomosis inhibits the expression of pulmonary angiotensin-converting enzyme and suppresses angiotensin II production.


OBJECTIVE
This study examines the role of the angiotensin II receptors, type 1 and type 2, in this setting of pulmonary vascular remodeling.


METHODS
Lambs, aged 40 to 50 days, underwent cavopulmonary anastomosis. In age-matched control animals, a sham operation was performed. Messenger RNA and protein expression in lung specimens was measured at successive time points after cavopulmonary anastomosis or sham operations (n = 3 at each time point).


RESULTS
Angiotensin type 1 mRNA was maximally upregulated 2-fold at 5 weeks after cavopulmonary anastomosis (P =.006). Expression of angiotensin type 1 protein was increased at least 2-fold at 2, 5, and 15 weeks after cavopulmonary anastomosis (P =.005). Cavopulmonary anastomosis also increased angiotensin type 2 mRNA and protein expression at least 2-fold at 2 and 5 weeks (P =.02) after surgical intervention. At 15 weeks, expression of angiotensin type 2 mRNA and protein was unchanged from that seen in control animals. Immunolocalization in pulmonary tissue sections 2 weeks after cavopulmonary anastomosis revealed markedly enhanced staining of angiotensin II receptor type 1 in vascular smooth muscle and angiotensin II receptor type 2 in the endothelium of pulmonary arteries.


CONCLUSIONS
Rapid elevation in the expression of the type 1 and 2 angiotensin II receptors in the affected pulmonary vasculature after cavopulmonary anastomosis suggests their involvement in the pathologic vascular remodeling that occurs after cavopulmonary anastomosis.
Malhotra
Sunil P
SP
Division of Cardiothoracic Surgery, University of California, San Francisco 94305-5407, USA.
Reddy
V Mohan
VM
Thelitz
Stephan
S
He
You-Ping
YP
Hanley
Frank L
FL
Suleman
Sam
S
Riemer
R Kirk
RK
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression; D018610:Heart Bypass, Right; D007150:Immunohistochemistry; D023421:Models, Animal; D008955:Models, Cardiovascular; D011651:Pulmonary Artery / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000096:biosynthesis* / Q000235:genetics; D012756:Sheep; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin