Edward Lakatta, M.D., Chief
We study an endogenous steroidal Na/K-ATPase inhibitor marinobufagenin (MBG), discovered in our laboratory in multiple species including humans. MBG is a pro-hypertensive and pro-fibrotic factor, implicated in human diseases, which include salt-sensitive hypertension, preeclampsia and chronic renal failure. MBG is synthetized in adrenocortical cells with the participation of a cytochrome P450 oxidase CYP27A1. MBG initiates TGF-beta- and/or Fli1-dependent pro-fibrotic signaling in cardiovascular, renal and placental tissues via binding to Na/K-ATPase. MBG levels are related to the salt-sensitivity in men and directly associated with arterial stiffness and levels of oxidative stress markers in older humans. Notably, that age-associated increase in salt-sensitivity, i.e. the blood pressure increase in response to dietary high salt intake, is accompanied by a shift in atrial natriuretic peptide (ANP) modulation of the MBG effect on vascular and renal Na/K-ATPase. We have developed an anti-MBG antibody, which reduced blood pressure in animal model of preeclampsia and, in addition to its anti-hypertensive effect, reversed cardiac and renal fibrosis in animal model of chronic renal failure. Recently we have discovered that central arterial stiffness and development of fibrosis in small cerebral arteries are associated with cognitive impairment in the animal model of an expedited aging.
List of Portfolio/Research Areas
- Endogenous steroidal Na/K-ATPase inhibitors, including bufadienolide MBG
- Age-associated changes in the relations of MBG and its receptor, Na/K-ATPase
- Cardiovascular, placental and renal fibrosis, and arterial stiffening in aging and in disease
- Human diseases involving MBG: salt-sensitive hypertension, myocardial infarction, preeclampsia, chronic renal failure
- Vascular dementia
Findings and Publications
Fedorova OV, Simbirtsev AS, Kolodkin NI, Kotov AY, Agalakova NI, Kashkin VA, Tapilskaya NI, Bzhelyansky AM, Reznik VA, Frolova EV, Budny GV, Longo DL, Lakatta EG, Bagrov AY. Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension. J Hypertens. 2008; 26:2414-2425.
Fedorova OV, Kashkin VA, Zakharova IO, Bagrov AY. Age-associated increase in salt sensitivity is accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump. J Hypertens. 2012; 30:1817-1826.
Jablonski KL, Fedorova OV, Racine ML, Geolfos CJ, Gates PE, Chonchol M, Fleenor BS, Lakatta EG, Bagrov AY, Seals DR. Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness. Clin J Am Soc Nephrol. 2013; 8:1952-1959.
Fedorova OV, Lakatta EG, Bagrov AY, Melander O. Plasma level of the endogenous sodium pump ligand marinobufagenin is related to the salt-sensitivity in men. J Hypertens. 2015; 33: 534-541.
Fedorova OV, Zernetkina VI, Shilova VY, Grigorova YN, Juhasz O, Wei W, Marshall CA, Lakatta EG, Bagrov AY. Synthesis of an endogenous steroidal Na pump inhibitor marinobufagenin, implicated in human cardiovascular diseases, is initiated by CYP27A1 via bile acid pathway. Circ Cardiovasc Genet. 2015; 8(5):736-745.