Left ventricular hypertrophy (LVH) in response to pressure overload is associated with increased cardiovascular morbidity and mortality, making its prevention an important therapeutic goal. The role of a calcineurin-dependent molecular pathway in the induction of pressure-overload LVH is controversial. The present study tested the hypothesis that, in the setting of LV pressure overload, activation of the systemic renin-angiotensin system was necessary for activation of this calcineurin pathway. Mild LV pressure overload was induced in male Wistar rats by abdominal aortic constriction (AAC) or transverse aortic arch constriction (TAC), producing well-matched pressure gradients of 37 ?? 8 and 35 ?? 15 mmHg, respectively. Tight transverse aortic arch constriction (TTAC) in additional animals produced a pressure gradient of 75 ?? 15 mmHg. Only AAC increased plasma renin concentration and activated the calcineurin pathway, indicated by increased nuclear NFAT3 content. Plasma renin concentration and nuclear NFAT3 content were unchanged in TAC and TTAC animals. AAC animals developed more LVH 21 days post-banding than TAC and TTAC animals: the slope of the relationship between LV/body weight ratio and systolic blood pressure was much steeper in AAC animals than the combined TAC and TTAC animals (20x10-6 versus 5x10-6, p<0.001). Treatment with the calcineurin inhibitor FK506 did not significantly alter the slope of this relationship in the combined TAC and TTAC animals (8x10-6), but FK506 abolished this relationship in AAC animals (-5x10-6, R =0.0003). These data indicate that activation of the calcineurin pathway occurs only in high-renin hypertension, providing an additional stimulus to LVH induction. Calcineurin plays no role in the induction of LVH in low-renin hypertension, which is much more common clinically.
| Identifer | oai:union.ndltd.org:ADTP/212692 |
| Date | January 2005 |
| Creators | Benson, Victoria Louise, St Vincent's Clinical School, UNSW |
| Publisher | Awarded by:University of New South Wales. St Vincent's Clinical School |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Victoria Louise Benson, http://unsworks.unsw.edu.au/copyright |
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