Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2012

Macrophage MR signalling regulates systolic blood pressure and cardiovascular remodelling (#88)

Jimmy Z Shen 1 2 , James Morgan 2 , Greg Tesch 3 , Peter J Fuller 1 4 , Morag J Young 2 5
  1. Endocrinology, Southern Health, Clayton, VIC, Australia
  2. Cardiovascular Endocrinology, Prince Henry's Institute, Clayton, VIC, Australia
  3. Nephrology, Southern Health, Clayton, VIC, Australia
  4. Steroid Receptor Biology, Prince Henry's Institute, Clayton, VIC, Australia
  5. Physiology, Monash University, Clayton, VIC, Australia

Background: Mineralocorticoid receptor (MR) activation in the presence of high salt promotes vascular and cardiac inflammation, remodeling and fibrosis1,2 .  A critical step in the development of fibrosis and tissue injury in this model is macrophage recruitment and vascular inflammation3,4 .  A recent study showed mice in which the macrophage MR is selectively deleted, are protected from hypertension and cardiac inflammation and fibrosis without apparent change in macrophage recruitment 5 .

Methods: We seek to verify this important role of macrophages by using mice in which monocyte chemoattractant protein 1 (MCP-1) is selectively deleted, thus impairing macrophage recruitment. This will independently interrogate the role of macrophages in mediating cardiac inflammation and fibrosis. Male mice from each genotype (wild type and MCP-1 -/-) were uninephrectomised, given 0.9% NaCl to drink and treated for 8 days or 8 weeks with either vehicle (n=6-8) or deoxycorticosterone (DOC) (n=6-10).

Results: At 8 weeks, a significant reduction in cardiac macrophage (>50%, p<0.005) and CD3+ T cells (>50%, p<0.01) density was observed in the MCP-1 -/- compared to wild type regardless of treatment. MCP-1 -/- mice given DOC showed no increase in systolic blood pressure or cardiac fibrosis at 8 weeks, in contrast to wild type mice (11% reduction in SBP and 30% reduction in cardiac collagen area, p<0.005). Cardiac hypertrophy was similar for each genotype. Expression of pro-oxidative and inflammatory genes was significantly reduced in the MCP-1 -/- mice in response to DOC. Expression of profibrotic markers (TGF-β1 and CTGF) showed a significant treatment effect with DOC in both genotypes which may be attributed to expression in other cell types in the myocardium.

Conclusion: Macrophage recruitment and activation play a significant role in the regulation of systolic blood pressure and cardiac remodeling and fibrosis.
 

  1. Young, M., Head, G. & Funder, J. Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. Am J Physiol 269, E657-662 (1995)
  2. Brilla, C.G. & Weber, K.T. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 120, 893-901 (1992)
  3. Young, M.J. Mechanisms of mineralocorticoid receptor-mediated cardiac fibrosis and vascular inflammation. Curr Opin Nephrol Hypertens 17, 174-180
  4. Rocha, R., et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. American Journal of Physiology - Heart and Circulatory Physiology 283, H1802-H1810 (2002)
  5. Rickard, A.J., et al. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension 54, 537-543 (2009)