Abstract
Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) 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 CM. Yet no factor on its own is known to coordinate CM polarized organization. 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. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. 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. 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. 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.
Highlights
Heart failure is the final common stage of most cardiopathies
We show that subcellular localization of cardiomyocyte junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn[3] OE mice, which provides a molecular explanation for impaired cardiomyocyte polarization in these mice
Mice overexpressing Pdzrn[3] (Pdzrn[3] OE) were generated by crossing reporter mice, which harbor a bidirectional Tet-promoter cassette with genes for PDZRN3-V5 and β galactosidase, with αMHCtTA mice to allow for specific expression of Pdzrn[3] in CM at birth. (Fig. 1b) We used Western blot to examine the expression pattern of ectopic PDZRN3 related to endogenous PDZRN3 levels during postnatal maturation
Summary
Cardiomyocytes (CM) 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. 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. Cardiomyocytes (CM) can be seen as highly polarized cells with specialized structures present only between the ends of each abutted cell, the intercalated disks (IDs) These regions provide cell-to-cell mechanical connections and mediate electrochemical c ommunication[1]. PCP pathways are important in polarized cell migration and organ morphogenesis through activation of cytoskeletal pathways, such as those involving the small GTPases RhoA and Rac, protein kinase C, and Jun N-terminal kinase. We aimed at a deeper understanding of the mechanisms governing postnatal establishment and maintenance of these IDs, and alterations during the development of heart failure
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