Aortic Fibrosis, Induced by High Salt Intake in the Absence of Hypertensive Response, is Reduced by a Monoclonal Antibody to Marinobufagenin.
BACKGROUND
Marinobufagenin (MBG) is an endogenous Na/K-ATPase inhibitor, a natriuretic and a vasoconstrictor. MBG is implicated in salt-sensitive hypertension, cardiac hypertrophy, and initiate the pro-fibrotic signaling. Previously it was demonstrated that immunoneutralization of an endogenous MBG by 3E9 anti-MBG-antibody (mAb) in vivo lowered blood pressure (BP) and reversed cardiac fibrosis in salt-sensitive, and in partially nephrectomized rats. In the present study, we investigated whether mAb alleviates vascular remodeling induced in normotensive rats on high salt intake.


METHODS
Wistar rats (5 months old) received normal (CTRL; n = 8) or high salt intake (2% NaCl in drinking water) for 4 weeks ( n = 16). Rats from the group on a high salt intake were administered vehicle (SALT; n = 8) or mAb (50 µg/kg) (SALT-AB; n = 8) during the last week of high salt diet. BP, erythrocyte Na/K-ATPase activity, levels of MBG in plasma and 24-hour urine, and sensitivity of aortic explants to the vasorelaxant effect of sodium nitroprusside (SNP) were measured. Aortic collagen abundance was determined immunohistochemically.


RESULTS
In SALT vs. CTRL, heightened levels of MBG were associated with inhibition of erythrocyte Na/K-ATPase in the absence of BP changes. High salt intake was accompanied by a 2.5-fold increase in aortic collagen abundance and by a reduction of sensitivity of aortic explants to the vasorelaxant effect of SNP following endothelin-1-induced constriction. In the SALT-AB group, all NaCl-mediated effects were reversed by immunoneutralization of MBG.


CONCLUSIONS
High salt intake in young normotensive rats can induce vascular fibrosis via pressure-independent/MBG-dependent mechanisms, and this remodeling is reduced by immunoneutralization of MBG.
National Institute on Aging, NIH, Baltimore, Maryland, USA; Federal Almazov Medical Research Centre, and Sechenov Institute of Evolutionary Physiology and Biochemistry, St Petersburg, Russia.
Yulia N
YN
Grigorova
National Institute on Aging, NIH, Baltimore, Maryland, USA;
Ondrej
O
Juhasz
National Institute on Aging, NIH, Baltimore, Maryland, USA;
Valentina
V
Zernetkina
National Institute on Aging, NIH, Baltimore, Maryland, USA;
Kenneth W
KW
Fishbein
National Institute on Aging, NIH, Baltimore, Maryland, USA;
Edward G
EG
Lakatta
National Institute on Aging, NIH, Baltimore, Maryland, USA;
Olga V
OV
Fedorova
National Institute on Aging, NIH, Baltimore, Maryland, USA; bagrova@mail.nih.gov.
Alexei Y
AY
Bagrov
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D002018:Bufanolides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D008297:Male; D017208:Rats, Wistar; D012982:Sodium, Dietary; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D002018:Bufanolides; D012982:Sodium, Dietary; D014665:Vasodilator Agents; C093896:marinobufagenin; D003094:Collagen
Na/K-ATPase; blood pressure; high salt intake; hypertention; marinobu fagenin; monoclonal antibody; vascular fibrosis.