Calcitonin, calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), and
amylin belong to a unique group of peptide hormones important for homeostasis in
diverse tissues. Calcitonin is essential for calcium balance whereas CGRP and
ADM are important for neurotransmission, and cardiovascular and respiratory
regulation. Based on phylogenetic analysis, we identified intermedin as a novel
member of the calcitonin/CGRP peptide family. Analysis of intermedin expression
indicated that intermedin is expressed primarily in the pituitary and
gastrointestinal tract. Intermedin increases cAMP production in SK-N-MC and L6
cells expressing endogenous CGRP receptors and competes with labeled CGRP for
binding to its receptors in these cells. In addition, treatment of 293T cells
expressing recombinant calcitonin receptor-like receptor (CRLR) and one of the
three receptor activity modifying proteins (RAMPs) showed that a CRLR/RAMP
receptor complex is required for intermedin signaling. In contrast to CGRP and
ADM, which exhibit a preferential stimulation of CRLR when coexpressed with
RAMP1 and RAMP2 or RAMP3, respectively, intermedin represents a nonselective
agonist for the RAMP co-receptors. In vivo studies demonstrated that intermedin
treatment leads to blood pressure reduction in both normal and spontaneously
hypertensive rats via interactions with the CRLR/RAMP receptors. Furthermore, in
vivo treatment in mice with intermedin leads to a suppression of gastric
emptying activity and food intake. Thus, identification of intermedin as a novel
member of the calcitonin/CGRP peptide family capable of signaling through the
CRLR/RAMP receptor complexes provides an additional player in the regulation of
peripheral tissues by CRLR, and will allow development of new therapeutic agents
for pathologies associated with diverse vascular and gastrointestinal
disorders.
Roh et al. J Biol Chem. 2004 Feb 20;279(8):7264-74.
Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related
peptide (CT/CGRP) family identified from human and other vertebrate tissues.
Preprointermedin can generate a 47-amino acid mature peptide (IMD(1-47)) and a
shorter 40-amino acid one (IMD(8-47)) by proteolytic cleavage. The present study
was designed to determine the protective effect of IMD on cardiac
ischemia/reperfusion (I/R) injury and its possible mechanism. Isolated rat
hearts were perfused on a Langendorff apparatus and subjected to 45-min global
ischemia and 30-min reperfusion. Cardiac function was measured. The release of
myocardial protein and lactate dehydrogenase (LDH) and the formation of
malondialdehyde (MDA) were assayed. Myocardial cAMP content was determined by
radioimmunoassay (RIA). Cardiac I/R induced a marked inhibition of cardiac
function and myocardial injury. Reperfusion with IMD significantly attenuated
the I/R injury. Compared with I/R alone, perfusion with 10(-8)mol/L IMD(1-47)
and IMD(8-47) induced a 36% and 33% increase in Delta left ventricular pressure
(DeltaLVP), 30% and 28% in maximal rate of increase of LV pressure (+LVdP/dt
max), and 34% and 31% in maximal rate of decrease of LV pressure (-LVdP/dt max),
respectively (all P<0.01) but an approximately 58% and 51% decrease in LV
diastolic pressure, respectively (P<0.01). In addition, perfusion with IMD
markedly attenuated the leakage of LDH, total protein and myoglobin from
myocardia compared with I/R alone. The contents of ventricular myocardia cAMP
after reperfusion with 10(-8)mol/L IMD(1-47) and IMD(8-47) were 130% and 91%
higher, respectively, than that with I/R alone (all P<0.01). However,
formations of myocardial MDA were 52% and 50% lower than that with I/R alone
(all P<0.01), respectively. Interestingly, the above IMD effects were similar
to those of adrenomedullin (10(-8)mol/L). These results suggest that IMD, like
adrenomedullin, exerts cardio-protective effects against myocardial I/R injury.
Yang et al. Peptides. 2005 Mar;26(3):501-7
Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related
peptide (CT/CGRP) family identified from human and other vertebrate tissues.
Preprointermedin (preproIMD) can generate a 47 amino acid mature peptide
(IMD(1-47)) and a shorter 40 amino acid one (IMD(8-47)) by proteolytic cleavage.
Amino acid sequence analysis showed that cleavage sites are located between two
basic amino acids at Arg93-Arg94, resulting in the production of
preproIMD(95-147), namely IMD(1-53). The present study was designed to observe
the effects of IMD(1-53) on cardiac function in ischemia/reperfusion (I/R)
injury in isolated rat hearts. Perfusion with high-dose IMD(1-53) gave higher
left ventricular systolic pressure (LVSP) and maximal rate of increase and
decrease of left ventricle pressure (+/-LVdP/dt(max)), and coronary perfusion
flow (CPF) than those of controls. Cardiac I/R induced a marked inhibition of
cardiac function and myocardial injury. Reperfusion with IMD(1-53) significantly
ameliorated the inhibited cardiac function and bradycardia induced by I/R.
Compared with the I/R-treatment alone, IMD(1-53) reperfusion augmented CPF,
LVSP, and maximal rate of increase and decrease of left ventricle pressure
(+/-LVdP/dt(max)) and decreased LVDP. In addition, reperfusion with
IMD(1-53)markedly attenuated the leakage of lactate dehydrogenase and
malondialdehyde content in myocardia compared with I/R alone. Reperfusion with
IMD(1-53)increased the content of cyclic adenosine monophosphate in comparison
with I/R alone. Interestingly, the above IMD(1-53) effects are similar to those
of adrenomedullin. These results suggest that IMD(1-53), like adrenomedullin,
has cardioprotective effects against myocardial I/R injury.
Yang et al. Biochem Biophys Res Commun. 2005 Feb 18;327(3):713-9
