Pacemaker cells meshwork the key player in the intercellular vesicles exchange within heart in young and old mice.

National Institute On Aging

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Abstract

Using live tissue imaging techniques, we detected a wide-ranging of vesicles with a size varying from 200 nm to 1-3 µm that have been released from dendritic and ameboid S100B-containing cells into the interstitial space of the sinoatrial node. The primary targets of the vesicular proteins were HCN4 positive pacemaker cells. We found EVs released from SAN interstitial cells with Ca2+-binding protein S100B and with transcriptional factor TBX3 protein. Tbx3 is known to suppress CX43 expression. Thereby, local vesicular release of TBX3 will create a group of cells without CX43. We found that expression of CX43 protein within heart is not homogeneous. The expression pattern of CX43 creates a gradient of expression from the SAN tissue with a low expression to the center of the right auricle with a higher expression of CX43. CX43 gradient determines gradient of electrical coupling between SAN and auricular cells. Thereby high impedance of the SAN tissue should block a reentry of action potentials propagating from the low impedance tissue of the right auricle in normal healthy mice. Conclusions: We discovered that the dendritic and ameboid interstitial cells release vesicles with diameter varying from 200 nm to 3 µm into interstitial space in vivo. The release of the S100B cardio-regulatory protein together with other cargo proteins like TBX3 from the interstitial cells to the extracellular space within SAN provides the mechanism by which SAN interstitial cells regulate phenotype and function of SAN pacemaker cells. Localized secretion of TBX3 targets HCN4+-immunoreactive cells and may suppress locally expression of CX43 protein. The gradient of CX43 expression found in right auricle strongly supports this hypothesis. Absences of the CX43 gradient expression may create a closed circuits within the heart, where impulses repeatedly stimulate chambers without allowing them to rest between heartbeats. The appearance of such the local circuits with age within heart may explain the mechanism of age-related reentry arrhythmia in which heart rhythm disturbance occurs when an electrical impulse takes an abnormal pathway instead of the usual one.