Cardiac sympathetic neurons provide trophic signal to the heart via β2-adrenoceptor-dependent regulation of proteolysis

Zaglia, Tania; Milan, Giulia; Franzoso, Mauro; Bertaggia, Enrico; Pianca, Nicola; Piasentini, Eleonora; Voltarelli, Vanessa Azevedo; Chiavegato, David; Brum, Patrícia Chakur; Glass, David J.; Schiaffino, Stefano; Sandri, Marco; Mongillo, Marco

doi:10.1093/cvr/cvs320

Cited by 80 publications

(105 citation statements)

References 53 publications

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“…This is not associated with hyperplasia rather because of increased size of cardiomyocytes, which does not change with isoproterenol treatment (Figures 3a and b). As cardiac sympathetic nervous system is a strong regulator of cardiomyocyte size via bAR-dependent repression of proteolysis, 47 we believe that this size increase is a function of elevated bAR activity in the absence of Bim, similar to the observation in thymocytes. Furthermore, this hypertrophy is not associated with any pathology, as we could not detect any upregulation of pathology-associated genes such as Myh6 and 7; Serca2 or Col1a1 and Col3a1.…”

Section: Discussionsupporting

confidence: 77%

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

et al. 2013

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Catecholamines regulate the b-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the b-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. Cell Death and Differentiation (2013) 20, 941-952; doi:10.1038/cdd.2013 published online 12 April 2013 Cyclic adenosine monophosphate (cAMP) is a second messenger that is highly conserved throughout evolution. In metazoans, its primary role is to act as an intracellular carrier of metabolic information, regulating hormonal responses, 1 in triggering apoptotic cell death and in regulating ontogeny.2,3

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Section: Discussionsupporting

confidence: 77%

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

et al. 2013

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“…The lowered LVID d is not surprising given the reductions to LV volumes, whereas the reductions to LV mass in SCI likely reflect myocardial atrophy due to myocardial unloading and a chronic loss of sympathetic tone,46 the latter of which plays an important trophic role in the heart. Ventricular unloading culminates from reductions to LV preload (eg, reduced venous return, total blood volume) and lowered LV afterload (eg, reduced wall stress and peripheral vascular tone47).…”

Section: Discussionmentioning

confidence: 99%

Cardiac consequences of spinal cord injury: systematic review and meta-analysis

Williams

Gee

Voss

et al. 2018

Heart

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ObjectiveConduct a meta-analysis to determine the impact of traumatic spinal cord injury (SCI) on echocardiographic measurements of left ventricular (LV) structure and function.MethodsMEDLINE and Embase were used for primary searches of studies reporting LV echocardiographic data in individuals with SCI. Of 378 unique citations, 36 relevant full-text articles were retrieved, and data from 27 studies were extracted for meta-analyses. Literature searches, article screening and data extraction were completed by two independent reviewers and compared for agreement. Primary analyses compared echocardiographic indices between individuals with SCI and able-bodied individuals, using a random effects model.ResultsData are reported as pooled effect estimates (95% CI). Data from 22 articles (474 participants) were included in the primary meta-analysis. Compared with able-bodied individuals, individuals with SCI had reductions to LV stroke volume of 11.8 mL (95% CI −17.8 to −5.9, p<0.001), end-diastolic volume of 19.6 mL (95% CI −27.2 to −11.9, p<0.001) and LV massindex of −7.7 g/m2 (95% CI −11.6 to −3.8, p<0.001), but ejection fraction was not different between the groups (95% CI −2.6% to 0.6%, p=0.236). Individuals with SCI also had altered indices of diastolic function, specifically a lowered ratio of early-to-late filling velocities (p=0.039), and augmented ratio of early diastolic flow-to-tissue velocities (p=0.021).ConclusionsIndividuals with SCI have smaller LV volumes and mass, and altered systolic and diastolic function. While this meta-analysis demonstrates important alterations to echocardiographic measures of cardiac structure and function at rest, future work should consider the impacts of SCI on the heart’s capacity or ‘reserve’ to respond to physiological challenges.PROSPERO registration numberCRD42017072333.

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“…Immunofluorescence analysis was performed as described in ref. 73. The following primary antibodies were used in this study: rabbit anti-cx40 (1:200, Invitrogen) and mouse anti-α-MyHC (1:200, clone BAG5) (74).…”

Section: Methodsmentioning

confidence: 99%

Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2

Zaglia

Pianca

Borile

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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101

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Extrasystoles lead to several consequences, ranging from uneventful palpitations to lethal ventricular arrhythmias, in the presence of pathologies, such as myocardial ischemia. The role of working versus conducting cardiomyocytes, as well as the tissue requirements (minimal cell number) for the generation of extrasystoles, and the properties leading ectopies to become arrhythmia triggers (topology), in the normal and diseased heart, have not been determined directly in vivo. Here, we used optogenetics in transgenic mice expressing ChannelRhodopsin-2 selectively in either cardiomyocytes or the conduction system to achieve cell typespecific, noninvasive control of heart activity with high spatial and temporal resolution. By combining measurement of optogenetic tissue activation in vivo and epicardial voltage mapping in Langendorffperfused hearts, we demonstrated that focal ectopies require, in the normal mouse heart, the simultaneous depolarization of at least 1,300-1,800 working cardiomyocytes or 90-160 Purkinje fibers. The optogenetic assay identified specific areas in the heart that were highly susceptible to forming extrasystolic foci, and such properties were correlated to the local organization of the Purkinje fiber network, which was imaged in three dimensions using optical projection tomography. Interestingly, during the acute phase of myocardial ischemia, focal ectopies arising from this location, and including both Purkinje fibers and the surrounding working cardiomyocytes, have the highest propensity to trigger sustained arrhythmias. In conclusion, we used cell-specific optogenetics to determine with high spatial resolution and cell type specificity the requirements for the generation of extrasystoles and the factors causing ectopies to be arrhythmia triggers during myocardial ischemia.optogenetics | heart | Purkinje fiber | arrhythmia | cardiac ectopies A berrant heartbeats, caused by the ectopic depolarization of a group of cardiomyocytes, are associated with a wide range of consequences, from the commonly experienced feeling of "palpitation" to the triggering of potentially lethal ventricular arrhythmias in diseased hearts. Physiological conduction of normal heartbeats is orchestrated by the interaction of at least two functionally and anatomically distinct populations of cardiomyocytes: the working cardiomyocytes and the conduction system (i.e., Purkinje fibers at the ventricular level) (1). The electrotonic coupling of myocardial cells protects the heart from abnormal excitation and allows the effect of spontaneous activity in sparse cardiomyocytes to be "sunk" by the surrounding myocardium. As a result, a minimal "critical" number of cardiomyocytes needs to simultaneously depolarize to prevail over such a protective mechanism and generate conducted beats (2-5). When this occurs, the source-sink mismatch (abnormal depolarization current/ myocardial electrotonic sink) is focally overcome, resulting in a premature ventricular contraction (PVC) that, in the presence of arrhythmogenic substrates, may e...

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Cardiac sympathetic neurons provide trophic signal to the heart via β2-adrenoceptor-dependent regulation of proteolysis

Cited by 80 publications

References 53 publications

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

Cardiac consequences of spinal cord injury: systematic review and meta-analysis

Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2

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