Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy.
Patients with chronic renal failure develop a "uremic" cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy, and systemic oxidant stress. Patients with chronic renal failure are also known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin (MBG). On this background, we hypothesized that elevations in circulating MBG may be involved in the cardiomyopathy. First, we observed that administration of MBG (10 microg/kg per day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. MBG infusion caused increases in conscious blood pressure, cardiac weight, and the time constant for left ventricular relaxation similar to partial nephrectomy. Decreases in the expression of the cardiac sarcoplasmic reticulum ATPase, cardiac fibrosis, and systemic oxidant stress were observed with both MBG infusion and partial nephrectomy. Next, rats were actively immunized against a MBG-BSA conjugate or BSA control, and partial nephrectomy was subsequently performed. Immunization against MBG attenuated the cardiac hypertrophy, impairment of diastolic function, cardiac fibrosis, and systemic oxidant stress seen with partial nephrectomy without a significant effect on conscious blood pressure. These data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.
Kennedy
David J
DJ
Department of Medicine, Medical University of Ohio, Toledo, OH 43614-5809, USA.
Vetteth
Sandeep
S
Periyasamy
Sankaridrug M
SM
Kanj
Mohamed
M
Fedorova
Larisa
L
Khouri
Samer
S
Kahaleh
M Bashar
MB
Xie
Zijian
Z
Malhotra
Deepak
D
Kolodkin
Nikolai I
NI
Lakatta
Edward G
EG
Fedorova
Olga V
OV
Bagrov
Alexei Y
AY
Shapiro
Joseph I
JI
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002018:Bufanolides / Q000097:blood* / Q000276:immunology / Q000494:pharmacology; D006332:Cardiomegaly / Q000517:prevention & control; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood; D007114:Immunization; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy / Q000379:methods; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D014511:Uremia / Q000150:complications*
D002018:Bufanolides; D006728:Hormones; C093896:marinobufagenin; D000251:Adenosine Triphosphatases