Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX

Sheykhzade, Majid; Abdolalizadeh, Bahareh; Koole, Cassandra; Pickering, Darryl S.; Dreisig, Karin; Johansson, Sara Ellinor; Abboud, Balsam Kadri; Dreier, Rasmus; Berg, Jais Oliver; Jeppesen, Jørgen; Sexton, Patrick M.; Edvinsson, Lars; Wootten, Denise; Sams, Anette

doi:10.1016/j.ejphar.2018.04.007

Cited by 14 publications

(18 citation statements)

References 31 publications

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“…α-CGRP is widely distributed in a variety of tissues in both mice and humans 29 and plays a key role as a vasodilator in regulating vascular tone and blood flow under pathophysiological conditions 30 . In addition, α-CGRP is now recognized to be a pleiotropic peptide that enhances heart 31 and skeletal muscle 32 contraction, regulates the growth of various cell types 15, 33 and suppresses gastric acid secretion 34 .…”

Section: Discussionmentioning

confidence: 99%

Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes

Wan

Ceci

et al. 2019

Laboratory Investigation

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Background: α-Calcitonin gene-related peptide (α-CGRP) is a 37-amino acid neuropeptide involved in several pathophysiological processes. α-CGRP is involved in the regulation of cholangiocyte proliferation during cholestasis. In this study, we aimed to evaluate if α-CGRP regulates bile duct ligation (BDL)-induced liver fibrosis by using a α-CGRP knockout (α-CGRP −/− ) mouse model. Methods: α-CGRP −/− and wild-type (WT) mice were subjected to sham surgery or BDL for 7 days. Then, liver fibrosis and cellular senescence as well as the expression of kinase such as p38 and C-Jun N-terminal protein kinase (JNK) in mitogen-activated protein kinases (MAPK) signaling pathway were evaluated in total liver, together with measurement of cellular senescence in cholangiocytes or hepatic stellate cells (HSCs). Results: There was enhanced hepatic expression of Calca (coding α-CGRP) and the CGRP-receptor components (CRLR, RAMP-1 and RCP) in BDL and in both WT α-CGRP −/− and BDL α-CGRP −/− mice, respectively. Moreover, there was increased CGRP serum levels and hepatic mRNA expression of CALCA and CGRP receptor components in late-stage PSC samples compared to healthy control samples. Depletion of α-CGRP reduced liver injury and fibrosis in BDL mice that was associated with enhanced cellular senescence of hepatic stellate cells and reduced senescence of cholangiocytes as well as decreased activation of p38 and JNK MAPK signaling pathway. Cholangiocyte supernatant from BDL α-CGRP −/− mice inhibited the activation and increased cellular senescence of cultured human HSCs (HHSCs) compared to HHSCs stimulated with BDL cholangiocyte supernatant. Taken together, endogenous α-CGRP promoted BDL-induced cholestatic liver fibrosis through differential changes in senescence of HSCs and cholangiocytes and activation of p38 and JNK signaling. Modulation of α-CGRP/CGRP receptor signaling may be key for the management of biliary senescence and liver fibrosis in cholangiopathies.

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Section: Discussionmentioning

confidence: 99%

Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes

Wan

Ceci

et al. 2019

Laboratory Investigation

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“…This α analog had an extended half-life in serum (~7 h) and exhibited similar pharmacological properties to native αCGRP in isolated human and rodent vasculature. Similar to native α-CGRP, the acylated αCGRP-induced vasodilation was reversed with similar potencies by the addition of a CGRP receptor antagonist BIBN4096BS (Sheykhzade et al, 2018). Novo Nordisk has also developed another α-CGRP agonist, Serinyl-α-CGRP (2–37)-amide, consisting of an albumin-binding fatty acid moiety in the N-terminus.…”

Section: α-Calcitonin Gene-related Peptide As a Therapeutic Agentmentioning

confidence: 99%

“…These approaches will be helpful to extend the bioavailability of α-CGRP for longer duration of time in plasma. In recent years, the development of α-CGRP agonist with a longer half-life and bioavailability has been developed (Nilsson et al, 2016; Aubdool et al, 2017; Sheykhzade et al, 2018). Aubdool et al (2017) tested an acylated form of α-CGRP (developed by Novo Nordisk) in rodent models of hypertension and heart failure.…”

Section: α-Calcitonin Gene-related Peptide As a Therapeutic Agentmentioning

confidence: 99%

Protective Role of α-Calcitonin Gene-Related Peptide in Cardiovascular Diseases

2019

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α-Calcitonin gene-related peptide (α-CGRP) is a regulatory neuropeptide of 37 amino acids. It is widely distributed in the central and peripheral nervous system, predominantly in cell bodies of the dorsal root ganglion (DRG). It is the most potent vasodilator known to date and has inotropic and chronotropic effects. Using pharmacological and genetic approaches, our laboratory and other research groups established the protective role of α-CGRP in various cardiovascular diseases such as heart failure, experimental hypertension, myocardial infarction, and myocardial ischemia/reperfusion injury (I/R injury). α-CGRP acts as a depressor to attenuate the rise in blood pressure in three different models of experimental hypertension: (1) DOC-salt, (2) subtotal nephrectomy-salt, and (3) L-NAME-induced hypertension during pregnancy. Subcutaneous administration of α-CGRP lowers the blood pressure in hypertensive and normotensive humans and rodents. Recent studies also demonstrated that an α-CGRP analog, acylated α-CGRP, with extended half-life (~7 h) reduces blood pressure in Ang-II-induced hypertensive mouse, and protects against abdominal aortic constriction (AAC)-induced heart failure. Together, these studies suggest that α-CGRP, native or a modified form, may be a potential therapeutic agent to treat patients suffering from cardiac diseases.

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“…In an abdominal aortic constriction model of heart failure, the CGRP analog attenuated cardiac hypertrophy and apoptosis, demonstrating a beneficial effect of chronic CGRP treatment in heart failure over several weeks ( Aubdool et al, 2017 ). In human tissue, this analog also demonstrated similar pharmacological effects to the native peptide, except for a slightly reduced potency but a longer plasma half-life means that it is potentially useful in research as well as therapy ( Sheykhzade et al, 2018 ). Thus, CGRP analogs or agonism may be a viable pharmacological target for the treatment of cardiovascular diseases and warrants further study.…”

Section: Therapeutic Approaches Involving the Cgrp Pathwaymentioning

confidence: 99%

The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects

2018

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Calcitonin gene-related peptide (CGRP) is a highly potent vasoactive peptide released from sensory nerves, which is now proposed to have protective effects in several cardiovascular diseases. The major α-form is produced from alternate splicing and processing of the calcitonin gene. The CGRP receptor is a complex composed of calcitonin like receptor (CLR) and a single transmembrane protein, RAMP1. CGRP is a potent vasodilator and proposed to have protective effects in several cardiovascular diseases. CGRP has a proven role in migraine and selective antagonists and antibodies are now reaching the clinic for treatment of migraine. These clinical trials with antagonists and antibodies indicate that CGRP does not play an obvious role in the physiological control of human blood pressure. This review discusses the vasodilator and hypotensive effects of CGRP and the role of CGRP in mediating cardioprotective effects in various cardiovascular models and disorders. In models of hypertension, CGRP protects against the onset and progression of hypertensive states by potentially counteracting against the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic system. With regards to its cardioprotective effects in conditions such as heart failure and ischaemia, CGRP-containing nerves innervate throughout cardiac tissue and the vasculature, where evidence shows this peptide alleviates various aspects of their pathophysiology, including cardiac hypertrophy, reperfusion injury, cardiac inflammation, and apoptosis. Hence, CGRP has been suggested as a cardioprotective, endogenous mediator released under stress to help preserve cardiovascular function. With the recent developments of various CGRP-targeted pharmacotherapies, in the form of CGRP antibodies/antagonists as well as a CGRP analog, this review provides a summary and a discussion of the most recent basic science and clinical findings, initiating a discussion on the future of CGRP as a novel target in various cardiovascular diseases.

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Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX

Cited by 14 publications

References 31 publications

Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes

Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes

Protective Role of α-Calcitonin Gene-Related Peptide in Cardiovascular Diseases

The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects

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