Adrenomedullin inhibits vascular calcification
Department of Physiology and Pathophysiology, Peking University Health Science Center
Key Laboratory of the Ministry of Education on Molecular Cardiology
Yong-Fen Qi
Vascular
calcification
Hypertension
Diabetes
Mellitus
Hyperlipemia
Renal Failure
Aging
Media
Intima
Vascular calcification is believed to be an important risk factor of cardiovascular
diseases
Atherosclerosis
Vasoactive peptides:
Adrenomedullin
?
Adrenomedullin (ADM) is a peptide capable of inducing a potent and long lasting hypotensive effect
ADM is mainly synthesized and secreted from vascular endothelial and smooth muscle cells (VSMC)
ADM has been shown to have vasodilatory, hypotensive and growth regulating properties,
Exogenous ADM or ADM gene delivery attenuated hypertension and protected against cardiovascular remodeling, but ADM gene knockout resulted in higher blood pressure and cardiovascular abnormalities.
Endogenous ADM is an important factor in regulating cardiovascular and renal homoestasis, and is a potent cardio-reno-protective factor
receptors bound with ADM were orphan L-1 and RDC-1 receptors
In addition, another orphan receptor named calcitonin receptor-like receptor (CRLR) could bind with ADM when receptor activity-modifying protein (RAMP)2 and/or RAMP3 existed on cellular membrane surface
Fig. 1. (A) Calcification of multicellular nodules. von Kossa staining
for calcification, showing positive staining as black/brown areas
within the main, large, nodular structure (original magnification 40×).
(B) Formation of multicellular nodules in culture phase contrast
microscopy showing rat VSMCs (original magnification 20×).
A
B
Table :General index of calcified VSMCs.( n=6, X±S.D.)
ALP: alkaline phosphatase. **p<0.01 vs.control.
**
ADM content in
calcified VSMC
ADM mRNA relative
amount in calcified VSMC
CRLR mRNA
RAMP2 mRNA
RAMP3 mRNA
β-actin mRNA
446 bp
416 bp
371 bp
291 bp
C CRLR C RAMP2 C RAMP3
Alterations of CRLR, RAMP2，RAMP3 mRNA in calcified VSMCs mRNA expression were determined by semi-quantitative RT-PCR analysis. CRLR: calcitonin receptor like receptor. RAMP: receptor activity modifying protein. **p<0.01,compared with control.
**
*
**
**
**
**
**
**
**
**
*
*
Exogenous ADM inhibit calcification of VSMC
#p<0.05, ##p<0.01, compared with the group having the same peptide
but no inhibitor. Calcifying: calcifying alone group; Ca-: calcifying;
ADM: Adrenomedullin.PKAI: protein kinase A inhibitor.
Effects of protein kinase A inhibitor on vascular calcification
von Kossa staining for myocardium and aorta
A and C: control; B and D: calcified myocardium and aorta respectively
A
B
C
D
General characteristics of calcification of myocardium and aorta in rats
Blood pressure and cardiac function of control and vascular calcification of rat.
ADM content in plasma, myocardium and aorta
Relative amount of ADM, CRLR, RAMP2 and RAMP3 mRNA
in myocardium and aorta of rats. *p<0.05,**p<0.01 vs control
Myocardium
Aorta
*p<0.05, VDN vs control; #p<0.05, VDN+ADM vs VDN and VDN+Ls
VDN: vitamin D3 plus nicotine; Ls: liposome; ADM: adrenomedullin
Adrenomedullin inhibits vascular calcification
*p<0.05, VDN vs control; ## p<0.01, VDN+ADM vs VDN and VDN+Ls
FigB: The Scatchard plots from 125I-ADM binding with vascular membrane
Vascular cAMP content
Fig. 1. Effect of ADM(27–52)
on calcific nodules in thoracic
aorta of rats (n =7/ group, all
von Kossa sections132).
None of calcific nodules
in control rats;
B. dispersed calcific nodules
in model rats;
C. dense calcific nodules
in model rats;
D. less dispersed calcific
nodules in ADM rats;
E. lest calcific nodules in
ADM and ADM(27–52) rats;
F. less dispersed calcific
nodules in ADM(27–52) rats.
Endogenous ADM was increased, ADM and its receptor gene expressions were upregulated in calcified VSMC and aorta
Exogenous ADM can inhibit vascular calcification
Mechanism of ADM inhibiting calcification might be involved in cAMP/PKA pathwasy
Fragments derived from ADM can also inhibit vascular calcification
Summary
Acknowledgements
Chao-shu Tang
Bin Geng
Jing Zhao
Fang Yu
Yong-zheng Pang
Bao-hong Zhang
Chun-shui Pan
Da-yong Cai
Sheng-ying Wu
Wei Jiang
Grants:
1. State Major Basic Research Development Program of the People’s
Republic of China (G2000056905)
2. the National Natural Science Foundation of China (30470693)
3. the Major Project of the Ministry of Education of
People’s Republic of China (105001).
4. the Beijing Natural Science Foundation (7052041)