These regions provide cell-to-cell mechanical connections and mediate electrochemical communication 1. 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 CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.Ĭardiomyocytes (CM) can be seen as highly polarized cells with specialized structures present only between the ends of each abutted cell, the intercalated disks (IDs). We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. A moderate CM overexpression of Pdzrn3 ( Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. Yet no factor on its own is known to coordinate CM polarized organization.
One of the hallmarks of heart failure is alterations in the contact sites between CM. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart.
Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. Heart failure is the final common stage of most cardiopathies.
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