New Insights into the Effect of Mineralocorticoids on Circulating Progenitor Cell Counts in Canine Models of Cardiovascular Disease: The Case for Accelerated Senescence

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Background: We have previously described a reduction in circulating progenitor cells (CPCs) in canine models of systolic LV dysfunction and DOCA-salt hypertension and demonstrated a close correlation with exogenous and endogenous mineralocorticoid excess. Telomere length is a surrogate for biological age, and has been shown to be impaired in cardiovascular disease. Aldosterone is proinflammatory and profibrotic and plays a key role in the pathogenesis of congestive cardiac failure. We hypothesized that aldosterone may mediate the observed depletion in circulating progenitor cells by a direct effect on telomerase activity in these cells resulting in accelerated senescence. Methods: Six young normal dogs were treated with DOCA at a dose of 1mg/kg/day IM for 10 days. Blood and bone marrow (by aspirate from the humeral head) were analyzed at baseline and at 10 days for CD34+ progenitor cell counts. Blood pressures were measured at 10 days at the time of acute hemodynamic study. CD34+ cells were isolated by magnetic cell separation from peripheral blood and bone marrow at baseline and at the time of acute study. Cells were lyzed and telomerase enzyme activity was detected and quantified with a real-time polymerase chain reaction assay. Results: Uninstrumented dogs treated with DOCA for 10 days exhibited a significant fall in CD34+ cell counts in peripheral blood comparing baseline values with those at 10 days (40±7 to 14±1 CD34+ cells/100μL buffy coat, p<0.05) but not in bone marrow (130±39 to 148±42 CD34+ cells/100μL buffy coat, p=NS). In vitro studies of these cells demonstrated evidence of decreased telomerase activity by real time PCR assay at the same timepoints (24.7±0.5 to 25.6±0.5 threshold cycle units, p<0.01) Conclusion: This is the first study to demonstrate that mineralocorticoid excess, even in normal animals, results in reduced CPC numbers and that this decrease is associated with decreased telomerase activity in these cells. This observation suggests that mineralocorticoids may induce accelerated senescence of circulating progenitor cells in vivo, a mechanism leading to their reduced survival and decline in numbers. Taken together, these findings suggest that neurohumoral activation may play a mechanistic role in the regulation of peripheral CD34+CPCs.