Project Details
Projekt
The heat shock proteins A4 (HSPA4) ameliorates pathological myocardial remodeling through improving protein homeostasis
Applicant
Dr. Belal Mohamed
Subject Area
Anatomy and Physiology
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 422222902
Protein quality control (PQC) depends on the collaboration between proper protein folding, which is mainly performed by molecular chaperones, and targeted proteolysis mediated by the ubiquitin-proteasome (UPS) system and autophagy. Proteinopathies are diseases caused by protein misfolding and characterized by abnormal protein aggregation. Post-mitotic cells such as cardiomyocytes cannot simply avoid protein misfolding by cell division or regeneration. An increased load of misfolded proteins in the heart may therefore contribute to a progression of myocardial dysfunction. Measures to improve PQC by pharmacological intervention represent a novel therapeutic potential to treat human proteopathies and thereby heart failure. As molecular chaperones, the heat shock proteins (HSPs) help to maintain the proper PQC in the cells. HSPA4 is a member of the HSP70 family that plays a role in cell survival under stress conditions. We have already shown that HSPA4 protein levels increase in pathologically-remodeled hearts. Interestingly, classical Hspa4 knockout (Hspa4-/-) mice show markedly increased pathological remodeling associated with the aggregation of polyubiquitinated proteins. Our data to date indicate that the accumulation of ubiquitin aggregates in Hspa4-/- hearts was not caused by a defect in the proteasome: 1.) More aggregation of ubiquitinated proteins were detected in In Hspa4-/- hearts in the detergent-insoluble fraction that is preferentially degraded by autophagy. 2.) Neither proteasome activity nor p53 protein level, a typical substrate of the proteasome, was differentially affected in Hspa4+/+ and Hspa4-/- hearts. 3.) An accumulation of autophagosomes was observed in Hspa4-/- hearts. Therefore, we want to deeply investigate the autophagy as a possible mechanism for the accumulation of protein aggregates, which may be responsible for the greatly increased pathological remodeling. For this purpose, we established in vitro HSPA4 overexpression using adenovirus, as well as HSPA4 knockdown using siRNA. Moreover, we are currently generating in vivo cardiomyocyte-specific HSPA4 overexpression using adeno-associated virus (AAV9). Using gain and loss-of-function approaches, we would like to explore the hypothesis that HSPA4 protein suppresses pathologic myocardial remodeling and delays the progression to heart failure, possibly by improving autophagy-mediated degradation of toxic, misfolded proteins. Moreover, we want to identify the transcription factors controlling Hspa4 expression.
DFG Programme
Research Grants
