Biology subjects

hatem, s.

Publications and source records attributed to hatem, s..

3 recordsLinked to original sources

bioRxiv2020

Repression of Pdzrn3 is required for heart maturation and protects against heart failure

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between cardiomyocytes. Yet no factor on its own is known to coordinate cardiomyocyte polarized organization. We report enhanced levels of an ubiquitine ligase Pdzrn3 in diseased hypertrophic human and mouse myocardium, which correlates with a loss of cardiomyocyte polarized elongation. We provide evidence that Pdzrn3 has a causative role in heart failure. We found that cardiac Pdzrn3 deficiency protected against heart failure while over expression of Pdzrn3 in mouse cardiomyocytes during the first weeks of life, impaired postnatal cardiomyocyte maturation leading to premature death. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of cardiomyocytes, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

physiology↗

bioRxiv2019

Microtubule polymerization state and clathrin-dependent internalization regulate dynamics of cardiac potassium channel

Ion channel trafficking powerfully influences cardiac electrical activity as it regulates the number of available channels at the plasma membrane. Studies have largely focused on identifying the molecular determinants of the trafficking of the atria-specific KV1.5 channel, the molecular basis of the ultra-rapid delayed rectifier current IKur. Besides, regulated KV1.5 channel recycling upon changes in homeostatic state and mechanical constraints in native cardiomyocytes has been well documented. Here, using cutting-edge imaging in live myocytes, we investigated the dynamics of this channel in the plasma membrane. We demonstrate that the clathrin pathway is a major regulator of the functional expression of KV1.5 channels in atrial myocytes, with the microtubule network as the prominent organizer of KV1.5 transport within the membrane. Both clathrin blockade and microtubule disruption result in channel clusturization with reduced membrane mobility and internalization, whereas disassembly of the actin cytoskeleton does not. Mobile KV1.5 channels are associated with the microtubule plus-end tracking protein EB1 whereas static KV1.5 clusters are associated with stable acetylated microtubules. In human biopsies from patients in atrial fibrillation associated with atrial remodeling, drastic modifications in the trafficking balance occurs together with alteration in microtubule polymerization state resulting in modest reduced endocytosis and increased recycling. Consequently, hallmark of atrial KV1.5 dynamics within the membrane is clathrin- and microtubule-dependent. During atrial remodeling, predominance of anterograde trafficking activity over retrograde trafficking could result in accumulation ok KV1.5 channels in the plasma membrane.

cell biology↗

bioRxiv2019

CELL SPECIFIC REACTIVATION OF EPICARDIUM AT THE ORIGIN OF FIBRO-FATTY REMODELING OF THE ATRIAL MYOCARDIUM

AbstractEpicardium, the mesothelium covering the heart, is composed of multipotent cells and is reactivated following myocardial injury in adults. Herein, we provide evidence for activation of atrial epicardium in aged patients with diseased atria and in murine models of atrial remodeling. Epicardial activation contributed to fibro-fatty infiltration of sub-epicardium that contained a number of cells co-expressing markers of epicardial progenitors and fibroblasts. Indeed, using genetic lineage tracing of adult epicardium, we demonstrate the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of adult epicardial-derived cells (aEPDCs) expressing PDGFR, niched in the sub-epicardium, were isolated and differentiated into myofibroblast in the presence of angiotensin-II. Furthermore, single cell RNA-seq analysis identified several clusters of aEPDCs and revealed transition from adipogenic to fibrogenic cells. In conclusion, a subset of aEPDCs, pre-programmed towards a specific cell fate, contributes to fibro-fatty infiltration of sub-epicardium of diseased atria.

pathology↗