Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazone.
Elevated oxidative stress has been characterized in numerous disorders including systemic hypertension, arterial stiffness, left ventricular hypertrophy (LVH) and heart failure. The peroxisome proliferator activated receptor gamma (PPARgamma) ameliorates oxidative stress and LVH. To test the hypothesis that PPARgamma decreased LVH and cardiac fibrosis in chronic pressure overload, in part, by increasing SOD, eNOS and elastin and decreasing NOX4, MMP and collagen synthesis and degradation, chronic pressure overload analogous to systemic hypertension was created in C57BL/6J mice by occluding the abdominal aorta above the kidneys (aortic stenosis-AS). The sham surgery was used as controls. Ciglitazone (CZ, a PPARgamma agonist, 4 microg/ml) was administered in drinking water. LV function was measured by M-Mode Echocardiography. We found that PPARgamma protein levels were increased by CZ. NOX-4 expression was increased by pressure-overload and such an increase was attenuated by CZ. SOD expression was not affected by CZ. Expression of iNOS was induced by pressure-overload, and such an increase was inhibited by CZ. Protein levels for MMP2, MMP-9, MMP-13 were induced and TIMP levels were decreased by pressure-overload. The CZ mitigated these levels. Collagen synthesis was increased and elastin levels were decreased by pressure-overload and CZ ameliorated these changes. Histochemistry showed that CZ inhibited interstitial and perivascular fibrosis. Echocardiography showed that CZ attenuated the systolic and diastolic LV dysfunction induced by pressure-overload. These observations suggested that CZ inhibited pressure-overlaod-induced cardiac remodeling, and inhibition of an induction of NOX4, iNOS, MMP-2/MMP-13 expression and collagen synthesis/degradation may play a role in pressure-overload induced cardiac remodeling.
Henderson
Brooke C
BC
Department of Physiology, Biophysics, University of Louisville, Louisville, KY 40202, USA.
Sen
Utpal
U
Reynolds
Corey
C
Moshal
Karni S
KS
Ovechkin
Alexander
A
Tyagi
Neetu
N
Kartha
Ganesh K
GK
Rodriguez
Walter E
WE
Tyagi
Suresh C
SC
D000818:Animals; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists*; D013482:Superoxide Dismutase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D003094:Collagen; D004549:Elastin; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D020782:Matrix Metalloproteinases; C039671:ciglitazone