Regulation of circulating progenitor cells in left ventricular dysfunction.
BACKGROUND
Reductions in numbers of circulating progenitor cells (CD34+ cell subsets) have been demonstrated in patients at risk for, or in the presence of, cardiovascular disease. The mediators of these reductions remain undefined. To determine whether neurohumoral factors might regulate circulating CD34+ cell subsets in vivo, we studied complementary canine models of left ventricular (LV) dysfunction.


RESULTS
A pacing model of severe LV dysfunction and a hypertensive renal wrap model in which dogs were randomized to receive deoxycorticosterone acetate (DOCA) were studied. Circulating CD34+ cell subsets including hematopoietic precursor cells (HPCs: CD34+/CD45(dim)/VEGFR2-) and endothelial progenitor cells (EPCs: CD34+/CD45-/VEGFR2+) were quantified. Additionally, the effect of mineralocorticoid excess on circulating progenitor cells in normal dogs was studied. The majority of circulating CD34+ cells expressed CD45dimly and did not express VEGFR2, consistent with an HPC phenotype. HPCs were decreased in response to pacing, and this decrease correlated with plasma aldosterone levels (Spearman rank correlation=-0.67, P=0.03). In the hypertensive renal wrap model, administration of DOCA resulted in decreased HPCs. No changes were seen in EPCs in either model. Normal dogs treated with DOCA exhibited a decrease in HPCs in peripheral blood but not bone marrow associated with decreased telomerase activity.


CONCLUSIONS
This is the first study to demonstrate that mineralocorticoid excess, either endogenous or exogenous, results in reduction in HPCs. These data suggest that mineralocorticoids may induce accelerated senescence of progenitor cells, leading to their reduced survival and decline in numbers.
Boilson
Barry A
BA
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn, USA.
Larsen
Katarina
K
Harbuzariu
Adriana
A
Delacroix
Sinny
S
Korinek
Josef
J
Froehlich
Harald
H
Bailey
Kent R
KR
Scott
Christopher G
CG
Shapiro
Brian P
BP
Boerrigter
Guido
G
Chen
Horng H
HH
Redfield
Margaret M
MM
Burnett
John C
JC
Simari
Robert D
RD
D000818:Animals; D018952:Antigens, CD34 / Q000097:blood*; D002304:Cardiac Pacing, Artificial; D003900:Desoxycorticosterone / Q000494:pharmacology; D004285:Dogs; D005434:Flow Cytometry; D006439:Hemodynamics; D017493:Leukocyte Common Antigens / Q000097:blood*; D008297:Male; D010641:Phenotype; D011863:Radioimmunoassay; D011897:Random Allocation; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D019098:Telomerase / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*; D018487:Ventricular Dysfunction, Left / Q000097:blood*
D018952:Antigens, CD34; D003900:Desoxycorticosterone; D040301:Vascular Endothelial Growth Factor Receptor-2; D019098:Telomerase; D017493:Leukocyte Common Antigens