Blood Pressure Normalization–Independent Cardioprotective Effects of Endogenous, Physical Activity–Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice
| Autor: | Katharyn J Mitchell, Max Gassmann, Johannes Vogel, Olga Vogel, Tom Skaria, Thomas Wälchli |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Normalization (statistics) medicine.medical_specialty Physiology Calcitonin Gene-Related Peptide Blood Pressure Endogeny Peptide Vasodilation Calcitonin gene-related peptide Mice Physical Conditioning Animal Internal medicine medicine Animals Cells Cultured Mice Knockout chemistry.chemical_classification medicine.disease Mice Inbred C57BL Treatment Outcome Blood pressure Endocrinology chemistry Calcitonin Heart failure Chronic Disease Hypertension Cardiology and Cardiovascular Medicine Biomarkers |
| Zdroj: | Circulation Research. 125:1124-1140 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Rationale: αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure. Objective: However, we hypothesize that endogenous, physical activity–induced αCGRP has blood pressure–independent cardioprotective effects in chronic hypertension. Methods and Results: Chronically hypertensive (one-kidney-one-clip surgery) wild-type 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. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type 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 blood pressure–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 patients with hypertension. |
| Databáze: | OpenAIRE |
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