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

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.

Clinical Application Effect of Cluster Management in Noninvasive Ventilator Nursing Care of Patients with Severe Heart Failure

“…Heart failure (HF) is a common cardiovascular disease that has a great impact on public health, with high medical costs, morbidity, and mortality [ 1 , 2 ]. According to the statistics of HF, the disease has affected 26 million cases, with the post-diagnosis 1-year and 5-year mortality rates as high as 45% and 60%, respectively [ 3 ].…”

Deep learning enabled analysis of cardiac sphericity

“…ANGPT1 has not been associated with cardiomyopathy to date, but mouse experiments have demonstrated a critical role in mammalian heart development 20,21 . The PDZRN3 locus has been previously associated with electrocardiographic characteristics 22 and LV fractal structure in prior GWAS 3 , and regulation of post-natal expression has been implicated in murine cardiac maturation and geometry 23 . The HLA DR/DQ locus has long been implicated in dilated cardiomyopathy 24,25 , and recent GWAS that included both normal and abnormal cardiac MRIs have identified this locus for both left and right chamber size metrics 2,26 .…”

Transcriptional Regulation of the Postnatal Cardiac Conduction System Heterogeneity

“…The 'Proximal VCS' zone showed high expression patterns of S100a6 encoding a Ca 2+ binding protein Calcyclin 66 , Col4a4, Alcam, Cdh6 and Atp1b2. Also, in addition to the established PF markers, Sema3a 67 and Gja5 68 , the 'Distal VCS' zone showed enrichment of Pdzrn3, involved in heart maturation 69 , Irx1 and Irx2 70 encoding Iroquois homeobox transcription factors, Mgp encoding Matrix Gla protein, Nsg2, and Sbk2. Interestingly, several PF and distal VCS genes, Mylk4, Corin, Sbk2 and Mgp, are also known to be expressed in the atria 71,72 .…”