Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice.

Ankush Borlepawar,Lynn Christen,Norbert Frey,Ashraf Yusuf Rangrez,Alexandra Rosskopf,Derk Frank,Renate Lüllmann-Rauch,Matthias Eden,Nesrin Schmiedel

doi:10.3390/cells9112390

Abstract

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

Highlights

Cardiac hypertrophy may be reversible and beneficial, adapting according to systemic demands such as exercise or pregnancy
We previously reported Dysbindin as a robust inducer of cellular hypertrophy via induction of
There was no effect of Dysbindin deficiency on hypertrophic gene program as assessed by the expressions of natriuretic peptides Nppa and Nppb and some of the known serum response factor (SRF) gene targets (Figure 1E,F and Figure S1C)

Summary

Introduction

Cardiac hypertrophy may be reversible and beneficial, adapting according to systemic demands such as exercise or pregnancy. Pathological hypertrophy induces cardiac remodeling including interstitial fibrosis, capillary rarefaction, increased production of pro-inflammatory cytokines, and cardiomyocyte dysfunction leading to advanced cardiomyopathy [3,4]. Among the multiple signaling pathways investigated over the last decades that are involved in cardiomyocyte hypertrophy and cardiomyopathy pathogenesis, induction of the cardiomyocyte hypertrophic gene program via the master transcription factor-serum response factor (SRF) is of crucial importance [5,6,7]. A cardiac enriched intercalated disc (ID) protein Myozap was reported to be a strong inducer of SRF-mediated cardiac hypertrophy [8]. Our group revealed several other key players like Dysbindin, GTPases like RhoA/Rnd, and TRIM family members like TRIM24/TRIM32, which lead to either induction or inhibition of SRF-signaling mediated cellular hypertrophy in neonatal rat cardiomyocytes.

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