S139ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S129–S144

Testosterone modulates physiological cardiac hypertrophyRuchi Patel1, Rebecca H. Ritchie1,2, Claire L. Curl2, Lea M.

Delbridge2, Igor R. Wendt1. 1Monash University. 2Universityof Melbourne, Australia

There is evidence for sex-based differences in the develop-ment of cardiac hypertrophy. In this study, we hypothesised thattestosterone exerts a pro-growth influence on the heart and,where there is genetic predisposition for cardiac hypertrophy,this effect would be more pronounced. A transgenic mousemodel in which hypertrophy is driven by cardiac-specific over-expression of angiotensinogen was used. Male wild-type (WT)and transgenic (TG) mice underwent gonadectomy (GDX) at12 weeks of age. Four weeks post surgery hearts were collectedand body weight, tibia length and heart weight determined.GDX significantly (p<0.05) inhibited heart growth in both WT(137±6 mg, Sham n=12, vs. 124±5 mg, GDX, n=12) and TG(155±4 mg, Sham n=15, vs. 135±7 mg, GDX, n=13 p<0.05)mice. Differences were maintained when heart weight wasnormalised to tibia length, however, not when it was normalisedto body weight (4.8±0.2 mg/g, WT Sham n=12, vs. 4.9±0.1 mg/g, WT GDX, n=12 and 5.3±0.1 mg/g, TG Sham n=15,vs. 5.2±0.2 mg/g, TG GDX, n=13). GDX had no detectableeffect on molecular markers of hypertrophy (βMHC or ANPgene expression) in either WT or TG mice. These resultsindicate that testosterone exerts a pro-growth effect on the heart,however, this response is proportional to body weight and islikely to be an influence on physiological hypertrophy. Since nodifferences were observed between WT and TG mice in res-ponse to GDX it is unlikely that testosterone exacerbates patho-logical hypertrophy in this model. Testosterone effects onpathological hypertrophy may only be evident in more severedisease states.

Keywords: Cardiac hypertrophy; Sex differences; Testosterone

doi:10.1016/j.yjmcc.2007.03.383

Na+/H+ exchanger over-expressing mice exhibithypertrophy and elevated response to phenylephrineFatima Mraiche1, Tracey Gan2, Morris Karmazyn2, LarryFliegel1. 1Depts of Biochem and Pediatrics, U of A. 2Depts ofPmcol, U of Western Ontario, Canada

The Na+/H+ exchanger isoform 1 (NHE1) is an integralmembrane protein, found in the myocardium. Recent evidenceshows that NHE1 is an important contributor to myocardialischemia/reperfusion injury and cardiac hypertrophy. NHE1levels are upregulated in several models of heart disease. α1

adrenoreceptor agonists, which are upregulated during heartfailure, enhance NHE1 activity and may potentiate the hyper-trophic response and heart failure. We examined the suscepti-bility of NHE1 over-expressing mice to hypertrophy with orwithout endocrine stimulation. NHE activity of adult ventricularcardiomyocytes was elevated in the NHE1 over-expressing

mice (350±12%) vs. controls (100±3.3%, P<0.05). The cellarea and the HW/BW ratio were larger in the transgenic mice(111±4.7% vs. controls 100±2.6%, P<0.05 and 130.4±4.6 vs.controls 100±3.8%, P<0.05), respectively. Transgenic andcontrol mice were then stimulated with phenylephrine (50 mg/kg/day) or PBS. The HW/BW ratio was elevated (160±7.1%,P<0.05) vs. controls (124.9±5.8%). Left ventricular cell dia-meter measurements were also elevated in transgenic mice(128.5±3.1, P<0.05) vs. controls (116.8±3.10). Atrial natriu-retic peptide mRNA levels showed a dramatic increase intransgenic mice (555.9±7.46%, P<0.001) vs. controls (141.3±8.86%). These results demonstrate that over-expression ofNHE1 is involved in the development of cardiac hypertrophyand that the hypertrophic response is accentuated in the pre-sence of phenylephrine.

Acknowledgment

Supported by CIHR.

Keywords: Na+/H+ exchanger; Phenylephrine; Cardiac hypertrophy

doi:10.1016/j.yjmcc.2007.03.384

Altered expression of myocardial [Ca2+] handling proteinsin experimental uraemiaDunja Aksentijević, Kian Y. Lee, Katie Smith, Sunil Bhandari,

Anne-Marie L. Seymour. Biological Sciences, University ofHull, Hull, UK

Cardiac complications, including left ventricular hypertrophy(LVH) are major factors in the increased cardiac mortalityobserved in patients with chronic kidney disease (CKD). How-ever, the impact of CKD on cardiac contractile function and Ca2+

handling is still unclear. The aim of this study was to examine theprofile of myocardial protein expression of Ca2+-ATPase(SERCA2a), phospholamban (PLB), Na+/K+-ATPase andANF in an experimental model of uraemia. Uraemia wasinduced in male Sprague–Dawley rats using two stage sub-totalnephrectomy. LV samples were harvested 6 weeks later andanalysed by SDS–PAGE andWestern blotting. Intensities of theprotein bands were quantified using Image-Pro Plus software.Uraemia was characterised by hypertrophy, impaired renalfunction (urea 15±3 vs. 6±1 mmol/L, p<0.001 n=17) andhypertension. Expression of ANF and Na+/K+-ATPase wassignificantly higher in uraemic hearts vs. control (ANF OD1.3±0.05 vs. 1±0.05; p<0.05 n=3; Na+/K+-ATPase OD 0.5±0.03 vs. 0.2±0.08; p<0.05 n=4). Uraemic LV tissue also exhi-bited a moderate reduction in SERCA2 expression and a smallincrease in PLB expression compared to control LV. Thus, theuraemic myocardium is characterised by significant haemody-namic abnormalities, LVH, cellular remodelling and alteredprotein expression. These adaptations may contribute to thelong term deterioration in cardiac function in uraemia resultingin heart failure.