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Regulation of myofibroblast differentiation and bleomycin-induced pulmonary
fibrosis by adrenomedullin
#MMPMID23585227
Kach J
; Sandbo N
; Sethakorn N
; Williams J
; Reed EB
; La J
; Tian X
; Brain SD
; Rajendran K
; Krishnan R
; Sperling AI
; Birukov K
; Dulin NO
Am J Physiol Lung Cell Mol Physiol
2013[Jun]; 304
(11
): L757-64
PMID23585227
show ga
Myofibroblast differentiation induced by transforming growth factor-? (TGF-?) is
characterized by the expression of smooth muscle ?-actin (SMA) and extracellular
matrix proteins. We and others have previously shown that these changes are
regulated by protein kinase A (PKA). Adrenomedullin (ADM) is a vasodilator
peptide that activates cAMP/PKA signaling through the calcitonin-receptor-like
receptor (CRLR) and receptor-activity-modifying proteins (RAMP). In this study,
we found that recombinant ADM had little effect on cAMP/PKA in quiescent human
pulmonary fibroblasts, whereas it induced a profound activation of cAMP/PKA
signaling in differentiated (by TGF-?) myofibroblasts. In contrast, the
prostacyclin agonist iloprost was equally effective at activating PKA in both
quiescent fibroblasts and differentiated myofibroblasts. TGF-? stimulated a
profound expression of CRLR with a time course that mirrored the increased PKA
responses to ADM. The TGF-? receptor kinase inhibitor SB431542 abolished
expression of CRLR and attenuated the PKA responses of cells to ADM but not to
iloprost. CRLR expression was also dramatically increased in lungs from
bleomycin-treated mice. Functionally, ADM did not affect initial differentiation
of quiescent fibroblasts in response to TGF-? but significantly attenuated the
expression of SMA, collagen-1, and fibronectin in pre-differentiated
myofibroblasts, which was accompanied by decreased contractility of
myofibroblasts. Finally, sensitization of ADM signaling by transgenic
overexpression of RAMP2 in myofibroblasts resulted in enhanced survival and
reduced pulmonary fibrosis in the bleomycin model of the disease. In conclusion,
differentiated pulmonary myofibroblasts gain responsiveness to ADM via increased
CRLR expression, suggesting the possibility of using ADM for targeting
pathological myofibroblasts without affecting normal fibroblasts.
|Actins/metabolism
[MESH]
|Adrenomedullin/*pharmacology/therapeutic use
[MESH]
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