Endothelial function in pigs transgenic for human complement regulating factor.
BACKGROUND
Expression of human complement regulating factor (hCRF) in porcine organs prevents hyperacute rejection of these organs after xenotransplantation to nonhuman primates. Experiments were designed to characterize endothelial and smooth muscle function of arteries from pigs transgenic for hCD46.


METHODS
Arterial blood from outbred pigs transgenic for hCD46 expression and nontransgenic animals of the same lineage was analyzed for angiotensin-converting enzyme (ACE), C-type natriuretic peptide (CNP), and nitric oxide. Aortic endothelial cells were prepared for measurement of mRNA or activity for nitric oxide synthase (NOS). Rings cut from femoral and pulmonary arteries were suspended in organ chambers for measurement of isometric tension.


RESULTS
CNP was significantly greater, ACE was similar, and nitric oxide was significantly less in plasma from transgenic compared with nontransgenic pigs. Neither mRNA nor activity of NOS differed between the groups. Endothelium-dependent relaxations to bradykinin and acetylcholine but not the calcium ionophore were shifted significantly to the left in femoral and pulmonary arteries from hCD46 transgenic pigs compared with nontransgenic pigs. The ACE-inhibitor captopril augmented relaxations similarly in both groups, but NG-monomethyl-L-arginine (L-NMMA) did not inhibit relaxations in rings from transgenic pigs.


CONCLUSIONS
Data suggest that expression of hCD46 on endothelium of pigs selectively augments endothelium-dependent relaxations to bradykinin by increased release of endothelium-derived factors other than nitric oxide. There does not seem to be any change in activity of ACE or NOS with expression of the human protein. Increased relaxations to bradykinin may be beneficial in lowering vascular resistance when transgenic organs are used for xenotransplantation.
Warnecke
Gregor
G
Division of Cardiothoracic Surgery and Transplantation, Department of Surgery, Mayo Clinic and Foundation, 200 First Street SW, Rochester MN 55905, USA.
Severson
Sandra R
SR
Ugurlu
Mustafa M
MM
Taner
Cemal B
CB
Logan
John S
JS
Diamond
Lisa E
LE
Miller
Virginia M
VM
McGregor
Christopher G A
CG
D000803:Angiotensin I / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D008297:Male; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000502:physiology*; D020098:Natriuretic Peptide, C-Type / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
D015703:Antigens, CD; C497857:CD46 protein, human; D019332:Endothelin-1; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D020098:Natriuretic Peptide, C-Type; D009569:Nitric Oxide; D000001:Calcimycin; D000803:Angiotensin I; D002216:Captopril; D019001:Nitric Oxide Synthase; D001920:Bradykinin