Title:Protective Effects of Intermedin On Cardiovascular, Pulmonary and Renal Diseases: Comparison with Adrenomedullin and CGRP
Volume: 14
Issue: 4
Author(s): David Holmes, Malcolm Campbell, Mark Harbinson and David Bell
Affiliation:
Keywords:
Adrenomedullin, CGRP, heart, hypertrophy, intermedin/adrenomedullin-2, ischaemia-reperfusion, kidney, oxidative
stress.
Abstract: Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the calcitonin gene-related peptide (CGRP) / adrenomedullin
(AM) family. The biological actions of this family are attributed to their actions at three receptor subtypes comprising
the calcitonin receptor-like receptor (CLR) complexed with one of three receptor activity modifying proteins. In contrast
to AM and CGRP, IMD binds non-selectively to all three receptor subtypes: CGRP, AM1, AM2. The peptide displays
an overlapping but differential and more restricted distribution across the healthy systemic and pulmonary vasculature,
heart and kidney relative to CGRP and AM. This, combined with tissue, regional and cell-type specific receptor expression,
underpins differences in regard to magnitude, potency and duration of haemodynamic, cardiac and renal effects of
IMD relative to those of AM and CGRP, and receptor-subtype involvement. In common with other family members, IMD
protects the mammalian vasculature, myocardium and kidney from acute ischaemia-reperfusion injury, chronic oxidative
stress and pressure-loading; IMD inhibits apoptosis, attenuates maladaptive tissue remodelling and preserves cardiac and
renal function. Robust upregulation of IMD expression in rodent models of cardiovascular and renal disease argues
strongly for the pathophysiological relevance of this particular counter-regulatory peptide. Such findings are likely to
translate well to the clinic: early reports indicate that IMD is expressed in and protects cultured human vascular and cardiac
non-vascular cells from simulated ischaemia-reperfusion injury, primarily via the AM1 receptor, and may have utility
as a plasma biomarker in cardiovascular disease. These observations should provide the rationale for short-term administration
of the peptide in acute disease, including myocardial infarction, cerebrovascular insult, cardiac and renal failure.