[Frontiers in Bioscience E2, 312-324, January 1, 2010]

Ablation of iNOS delays cardiac contractile dysfunction in chronic hypertension

Fernando A.L. Dias1,3, Dalia Urboniene2, Milana A. Yuzhakova2, Brandon J. Biesiadecki2, James R. Pena1, Paul H. Goldspink1,2, David L. Geenen1,2, Beata M. Wolska1,2

1Department of Medicine, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, USA, 2Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, USA, 3Department of Physiology and Department of Cell Biology, Federal University of Paraná, Curitiba, Brazil

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and Methods
3.1. Experimental animals
3.2. Induction of cardiac hypertrophy
3.3. Echocardiographic measurements
3.4. Hemodynamic measurements
3.5. Left ventricular papillary muscle experiments
3.6. Quantitative Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR)
3.7. Protein expression
3.8. Histology and immunofluorescence
3.9. Data computation and statistical analysis
4. Results
4.1. Expression and localization of iNOS
4.2. Effect of aortic banding (AoB) on the development of hypertrophy
4.3. Beta-adrenergic response in papillary muscles in short- and long-term AoB
4.4. Hemodynamic parameters in long-term WT-AoB and iNOSKO-AoB mice
4.5. Gene expression
4.6. Protein expression
5. Discussion
6. Acknowledgment
7. References

1. ABSTRACT

We investigated the role of inducible NOS (iNOS) on cardiac function during the development of left ventricular hypertrophy. Hypertrophy was induced by pressure-overload via short-term (2.5 months) or long-term (6.5 months) aortic banding (AoB) in wild-type (WT) and iNOS knock out (iNOSKO) mice. Cardiac function was then assessed via echocardiography, in situ hemodynamics and papillary muscle force measurements. Quantitative RT-PCR and Western blots were used to measure expression of hypertrophic gene markers and proteins respectively. Our data demonstrate that increased afterload via AoB leads to increased expression of iNOS that is associated with cardiac dysfunction. In pressure-overload induced hypertrophy, iNOSKO delays both the expression of hypertrophic markers and contractile dysfunction without causing significant changes in the level of hypertrophy. Moreover, after long-term AoB, iNOSKO animals exhibited increased basal cardiac function and an improved response to beta-adrenergic stimulation compared to long-term AoB WT animals. In conclusion, our data demonstrate that NO production via iNOS plays an important role in modulating cardiac function after moderate AoB that mimics long-term hypertension in humans.