Effects of adrenomedullin on cell proliferation in rat adventitia induced by aldosterone.
OBJECTIVE
Aldosterone is involved in cardiovascular diseases such as hypertension and heart failure by inducing sodium retention and vascular remodeling, which is characterized by fibroblast proliferation and migration in adventitia. It is well known that aldosterone stimulates vascular smooth muscle cells and fibroblasts to produce and secrete adrenomedullin (ADM), a multiple functional peptide with an important cytoprotective effect against cardiovascular damage. We examined the effect of aldosterone on ADM production and secretion and its mRNA expression in rat aortic adventitia to study the paracrine/autocrine interaction between endogenous ADM and aldosterone.


METHODS
ADM produced and secreted from adventitia stimulated by aldosterone in the absence or presence of spironolactone, RU486 or spironolactone together with RU486 were detected by radioimmunoassay, proliferation in adventitia cells was evaluated by the level of [H]-thymine incorporation, and preproADM gene expression was measured by semi-quantitative reverse transcriptase polymerase chain reaction.


RESULTS
Adventitial ADM secretion and mRNA expression stimulated by aldosterone were concentration-dependent as was the inhibitive effect of ADM on aldosterone-induced proliferation. The induction of aldosterone in ADM secretion was mediated by mineralocorticoid receptor. Antagonists of specific receptors of calcitonin gene-related peptide (CGRP) receptor type 1 and ADM both potentiated the proliferation effect induced by aldosterone; and thiorphan, an inhibitor of the enzyme for ADM degradation, inhibited the adventitial [H]-thymine incorporation induced by aldosterone. ADM inhibited the activity of extracellular signal related kinase (ERK) stimulated by aldosterone.


CONCLUSIONS
Aldosterone stimulates adventitia to produce and secrete ADM, which in turn, antagonizes the aldosterone-induced proliferation in adventitia.
Jiang
Wei
W
Institute of Cardiovascular Disease, Peking University First Hospital, Beijing 100034, China.
Yang
Jing-Hui
JH
Pan
Chun-Shui
CS
Qi
Yong-Feng
YF
Pang
Yong-Zheng
YZ
Tang
Chao-Shu
CS
D053607:Adrenomedullin; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009924:Organ Culture Techniques; D010455:Peptides / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013941:Thymine / Q000378:metabolism
D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; C112034:preproadrenomedullin; D053607:Adrenomedullin; D000450:Aldosterone; D048049:Extracellular Signal-Regulated MAP Kinases; D013941:Thymine