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Pernot M, Jaspard-Vinassa B, Abelanet A, et al. Decrease of Pdzrn3 is required for heart maturation and protects against heart failure. Sci Rep. 2022;12(1):8doi: 10.1038/s41598-021-03795-7.
Pernot, M., Jaspard-Vinassa, B., Abelanet, A., Rubin, S., Forfar, I., Jeanningros, S., Cetran, L., Yu, M. H., Balse, E., Hatem, S., Dufourcq, P., Couffinhal, T., & Duplàa, C. (2022). Decrease of Pdzrn3 is required for heart maturation and protects against heart failure. Scientific reports, 12(1), 8. https://doi.org/10.1038/s41598-021-03795-7
Pernot, Mathieu, et al. "Decrease of Pdzrn3 is required for heart maturation and protects against heart failure." Scientific reports vol. 12,1 (2022): 8. doi: https://doi.org/10.1038/s41598-021-03795-7
Pernot M, Jaspard-Vinassa B, Abelanet A, Rubin S, Forfar I, Jeanningros S, Cetran L, Yu MH, Balse E, Hatem S, Dufourcq P, Couffinhal T, Duplàa C. Decrease of Pdzrn3 is required for heart maturation and protects against heart failure. Sci Rep. 2022 Jan 07;12(1):8. doi: 10.1038/s41598-021-03795-7. PMID: 34996942; PMCID: PMC8742099.
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Sci Rep. 2022 Jan 07;12(1):8. doi: 10.1038/s41598-021-03795-7.

Decrease of Pdzrn3 is required for heart maturation and protects against heart failure.

Scientific reports

Mathieu Pernot, Béatrice Jaspard-Vinassa, Alice Abelanet, Sebastien Rubin, Isabelle Forfar, Sylvie Jeanningros, Laura Cetran, Murielle Han-Yee Yu, Elise Balse, Stéphane Hatem, Pascale Dufourcq, Thierry Couffinhal, Cécile Duplàa

Affiliations

  1. Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, 1 Avenue de Magellan, 33600, Pessac, France.
  2. Faculté de Médecine, Université Pierre et Marie Curie, Sorbonne University, INSERM UMR_S1166, Paris, France.
  3. Service de Biochimie Clinique, CHU de Bordeaux, Bordeaux, France.
  4. Service des Maladies Cardiaques et Vasculaires, CHU de Bordeaux, Bordeaux, France.
  5. Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, 1 Avenue de Magellan, 33600, Pessac, France. [email protected].

PMID: 34996942 PMCID: PMC8742099 DOI: 10.1038/s41598-021-03795-7

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.

© 2022. The Author(s).

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