Bone marrow angiotensin AT1 receptor regulates differentiation of monocyte lineage progenitors from hematopoietic stem cells.
BACKGROUND
The angiotensin II (Ang II) type 1 (AT(1)) receptor is expressed in bone marrow (BM) cells, whereas it remains poorly defined how Ang II regulates differentiation/proliferation of monocyte-lineage cells to exert proatherogenic actions.


RESULTS
We generated BM chimeric apoE(-/-) mice repopulated with AT(1)-deficient (Agtr1(-/-)) or wild-type (Agtr1(+/+)) BM cells. The atherosclerotic development was significantly reduced in apoE(-/-)/BM-Agtr1(-/-) mice compared with apoE(-/-)/BM-Agtr1(+/+) mice, accompanied by decreased numbers of BM granulocyte/macrophage progenitors (GMP:c-Kit(+)Sca-1(-)Lin(-)CD34(+)CD16/32(+)) and peripheral blood monocytes. Macrophage-colony-stimulating factor (M-CSF)-induced differentiation from hematopoietic stem cells (HSCs:c-Kit(+)Sca-1(+)Lin(-)) to promonocytes (CD11b(high)Ly-6G(low)) was markedly reduced in HSCs from Agtr1(-/-) mice. The expression of M-CSF receptor c-Fms was decreased in HSCs/promonocytes from Agtr1(-/-) mice, accompanied by a marked inhibition in M-CSF-induced phosphorylation of PKC-delta and JAK2. c-Fms expression in HSCs/promonocytes was mainly regulated by TNF-alpha derived from BM CD45(-)CD34(-) stromal cells, and Ang II specifically regulated the TNF-alpha synthesis and release from BM stromal cells.


CONCLUSIONS
Ang II regulates the expression of c-Fms in HSCs and monocyte-lineage cells through BM stromal cell-derived TNF-alpha to promote M-CSF-induced differentiation/proliferation of monocyte-lineage cells and contributes to the proatherogenic action.
Tsubakimoto
Yoshinori
Y
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566 Japan.
Yamada
Hiroyuki
H
Yokoi
Hirokazu
H
Kishida
Sou
S
Takata
Hiroki
H
Kawahito
Hiroyuki
H
Matsui
Akihiro
A
Urao
Norifumi
N
Nozawa
Yoshihisa
Y
Hirai
Hideyo
H
Imanishi
Jiro
J
Ashihara
Eishi
E
Maekawa
Taira
T
Takahashi
Tomosaburo
T
Okigaki
Mitsuhiko
M
Matsubara
Hiroaki
H
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D053614:Janus Kinase 2 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000032:analysis; D011973:Receptors, LDL / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D016173:Macrophage Colony-Stimulating Factor; C497259:Prkcd protein, mouse; D016186:Receptor, Macrophage Colony-Stimulating Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051745:Protein Kinase C-delta