Intermedins

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Introduction

Intermedin (IMD), is a new type of cardiovascular regulatory peptide found in recent years. It is a new member of calciton gene related peptide (CGRP) also including calcitonin (CT), adrenomedullin (ADM), α-CGRP, β-CGRP and amylin. The gene and protein structure of IMD are the same as those of amino acid sequence, nucleotide sequences, and biological activities of ADM-2 discovered in the mammal, and they are be sure the same substance. Multiple protease cleavage sites are distributed on the IMD precursor consists of 148 amino acid residues, which are cleaved in vivo to IMD_1-47 containing 47 amino acids, IMD_8-47 containing 40 amino acids, and active fragment of IMD_1-53.

Mechanism of IMD

IMD works through the calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein (RAMP) receptor complex (CRLR-RAMP), in which the CRLR is a G protein coupled receptor and is not a specific receptor protein of CGRP family and it only has receptor function when it binds to RAMPs. As we all know, RAMPs have three subtypes including RAMP1, RAMP2 and RAMP3, and IMD has a unique receptor binding property of combining with CRLR/RAMPs1-3. In addition to the CRLR/RAMPs system, IMD may also bind to CGRP receptors to exert its biological effects. Besides, IMD can activate the cyclic adenosine monophosphate (cAMP) signaling pathway, which is an important pathway for biological effects, and can participate in myocardial contraction, vasodilation and regulate biological effects such as cell proliferation, hypertrophy, migration, and apoptosis. Furthermore, ADM has a strong ability to promote NO synthesis, and the NO mediates its effects on vasodilation, inhibition of cell proliferation, differentiation and anti-apoptosis, and plays an important role in the occurrence and development of cardiovascular diseases and the maintenance of vascular homeostasis. Since IMD is similar to ADM and is endothelium dependent, it is speculated that IMD also has the effect of upregulating NO, and at the same time, it was confirmed that IMD_1-53 mainly increased the synthesis of NO and the activity of nitric oxide synthase (NOS) in rat aorta by increasing the activity of endothelial NOS (eNOS), and the effect was stronger than that of ADM.

Application of IMD

Owing to the special features of IMD, it is widely distributed and plays important roles in many tissues, especially in the cardiovascular system, which is involved in regulating blood pressure, promoting angiogenesis, protecting endothelial barrier function, and the pathogenesis of many diseases, such as arteriosclerosis, hypertension and vascular calcification. Therefore, IMD has become a promising target for the treatment of cardiovascular disease.

References

1. Holmes, D., Campbell, M., Harbinson, M., & Bell, D. (2013). Protective effects of intermedin on cardiovascular, pulmonary and renal diseases: comparison with adrenomedullin and CGRP. Current Protein & Peptide Science, 14(4), 294-329.
2. Bell, D., & Mcdermott, B. J. (2010). Intermedin (adrenomedullin-2): a novel counter-regulatory peptide in the cardiovascular and renal systems. British Journal of Pharmacology, 153(S1), S247-S262.