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Blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced alpha Calcitonin Gene-Related Peptide (αCGRP) in chronically hypertensive mice


Skaria, Tom; Mitchell, Katharyn J; Vogel, Olga; Wälchli, Thomas; Gassmann, Max; Vogel, Johannes (2019). Blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced alpha Calcitonin Gene-Related Peptide (αCGRP) in chronically hypertensive mice. Circulation Research, 125(12):1124-1140.

Abstract

Rationale: α-calcitonin gene related peptide (αCGRP), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure (BP). Objective: However, we hypothesize that endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects in chronic hypertension. MMethods and Results: Chronically hypertensive (one-kidney-one-clip surgery) WT and αCGRP-/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular and histological analysis, respectively. BP was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive WT mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP-/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling. Conclusions: Endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients.

Abstract

Rationale: α-calcitonin gene related peptide (αCGRP), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure (BP). Objective: However, we hypothesize that endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects in chronic hypertension. MMethods and Results: Chronically hypertensive (one-kidney-one-clip surgery) WT and αCGRP-/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular and histological analysis, respectively. BP was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive WT mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP-/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling. Conclusions: Endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
05 Vetsuisse Faculty > Veterinary Clinic > Equine Department
04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurosurgery
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Physiology
Health Sciences > Cardiology and Cardiovascular Medicine
Language:English
Date:6 December 2019
Deposited On:16 Dec 2019 12:09
Last Modified:29 Jul 2020 12:01
Publisher:Lippincott Williams & Wilkins
ISSN:0009-7330
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1161/CIRCRESAHA.119.315429
PubMed ID:31665965
Project Information:
  • : FunderSNSF
  • : Grant ID310030_160104
  • : Project TitleNew (patho-)physiological aspects of Calcitonin receptor-like receptor signaling: Can calcitonin gene-related peptide-(CGRP)-agonism inhibit pathological heart remodeling induced by chronic hypertension?
  • : FunderNovartis Foundation
  • : Grant ID16A012
  • : Project Title
  • : FunderKurt und Senta Herrmann Foundation
  • : Grant ID
  • : Project Title

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