Macrophage MR signalling regulates systolic blood pressure and cardiovascular remodelling (#88)
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.
- Young, M., Head, G. & Funder, J. Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. Am J Physiol 269, E657-662 (1995)
- Brilla, C.G. & Weber, K.T. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 120, 893-901 (1992)
- Young, M.J. Mechanisms of mineralocorticoid receptor-mediated cardiac fibrosis and vascular inflammation. Curr Opin Nephrol Hypertens 17, 174-180
- 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)
- 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)