Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia

Abstract

Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major contributor to population mortality and morbidity, particularly stroke-risk. 1 Atrialtissue fibrosis is a central pathophysiological feature and hampers AF-treatment; the underlying molecular mechanisms are poorly understood and present therapies are inadequate. 2 Here, we show that calcitonin (CT), a well-recognized hormone product of the thyroid gland involved in bone metabolism, 3 is produced in significant quantities by atrial cardiomyocytes and acts in a paracrine fashion on neighbouring collagenproducing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of CT-receptor signalling in mice causes atrial fibrosis and increases AF susceptibility. Atrial-specific knockdown (KD) of CT in atrial-targeted liver-kinase B1 (LKB1)-KD mice promotes atrial fibrosis and prolongs/increases the number of spontaneous AF-episodes, while atrial-specific CT overexpression prevents fibrosis and AF in LKB1-KD mice. Patients with persistent AF are characterised by six-

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe

“…Disruption of calcitonin receptor signaling in mouse atria led to fibrosis and increased atrial fibrillation risk. Importantly, these findings were recapitulated in humans, since atrial fibrillation patients were found to have sixfold lower levels of myocardial calcitonin and lower fibroblast membrane calcitonin receptor densities, compared with healthy control individuals [135]. Whether this beneficial calcitonin signaling in cardiac atria is also involved in modulation of PNS or SNS activity in the heart remains to be determined.…”

“…associated fibroblasts [135]. Disruption of calcitonin receptor signaling in mouse atria led to fibrosis and increased atrial fibrillation risk.…”

“…One very recent study reported that intermedin, a CGRP‐like calcitonin‐related peptide, may protect cardiomyocytes against sarcoplasmic reticulum stress and cardiac apoptosis via, in part, PKA and subsequent SERCA activation [134]. Finally, the hormone calcitonin itself was very recently reported to be released by atrial cardiomyocytes to induce, in a paracrine manner, proliferation of and extracellular matrix protein secretion from closely associated fibroblasts [135]. Disruption of calcitonin receptor signaling in mouse atria led to fibrosis and increased atrial fibrillation risk.…”

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation

“… 196 Extra-thyroidal CT expression is present in organs, such as the brain, uterus, prostate, and central nervous system. 197 , 198 We recently discovered that atrial cardiomyocytes actively produce CT. 199 Regardless of where CT is produced, it exerts its effects via binding to the CT receptor (CTR), 200 the seven-transmembrane domain class II (family B) G protein-coupled receptor that can couple to Gs, Gi, or Gq proteins. 201 , 202 The CTRs are expressed in tissues such as kidneys, 203 , osteoclasts, 204 skeletal muscle, 205 and recently identified in human atrial fibroblasts.…”

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

“…Patients with persistent AF, showed sixfold lower levels of calcitonin compared to controls with sinus rhythm and disruption of calcitonin signaling in mice triggered fibrogenesis and arrhythmias. Additionally, atrial specific overexpression of calcitonin in mice protected from fibrosis, highlighting a potential new treatment option for fibrosis [34]. Variations in connexin expression and function have been identified as another substrate causing conduction abnormalities.…”