Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure.
BACKGROUND
Diastolic heart failure is a rising problem with a high incidence and similar mortality and morbidity compared to patients with systolic heart failure. Nevertheless, the underlying pathophysiology is still debated.


OBJECTIVE
We investigated the effect of pharmacological enhancement of endothelial nitric oxide synthase (eNOS) on experimental diastolic heart failure (DHF).


METHODS
DHF was induced in 60 DAHL salt-sensitive rats by salt diet in 8-week-old animals. 30 were treated with the eNOS enhancer AVE3085 (DHFeNOS) and 30 with placebo (DHF). Rats with normal salt intake served as controls.


CONCLUSIONS
Diastolic dysfunction with increased diastolic stiffness constant and increased left ventricular (LV) pressure was analyzed by invasive pressure-volume loop measurements in the DHF group compared to controls. Cardiac hypertrophy as indicated by LV mass measurements by echocardiography, and increased cardiac collagen content as measured by immunohistochemistry were associated with an increased activation state of calcineurin, AKT, ERK(1/2), but not JNK and p38 kinases. Titin isoforms were not altered in this model of DHF. Treatment with AVE3085 significantly increased eNOS mRNA and protein levels in the cardiac tissue and decreases NAD(P)H oxidase subunits p22phox and gp91phox. Diastolic dysfunction was attenuated and cardiac hypertrophy and fibrosis were improved in comparison with untreated DHF animals. This was associated with a normalized activation state of calcineurin, AKT and ERK(1/2). Therefore, we suggest that targeting the NO system might yield a future therapeutic aim for the treatment of DHF.
Westermann
Dirk
D
Department of Cardiology and Pneumology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Riad
Alexander
A
Richter
Utz
U
Jäger
Sebastian
S
Savvatis
Konstantinos
K
Schuchardt
Mirjam
M
Bergmann
Nora
N
Tölle
Markus
M
Nagorsen
Dirk
D
Gotthardt
Michael
M
Schultheiss
Heinz-Peter
HP
Tschöpe
Carsten
C
D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D054144:Heart Failure, Diastolic / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction / Q000187:drug effects; D012965:Sodium Chloride; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
C528910:2,2-difluorobenzo(1,3)dioxole-5-carboxylic acid indan-2-ylamide; D052117:Benzodioxoles; D002316:Cardiotonic Agents; D007189:Indans; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D009569:Nitric Oxide; D012965:Sodium Chloride; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019703:Calcineurin