The Role of Heat Shock Protein A4 (HSPA4) in the Heart
by Daniel Marques Rodrigues
Date of Examination:2023-02-02
Date of issue:2023-07-07
Advisor:Prof. Dr. Karl Toischer
Referee:Prof. Dr. Susanne Lutz
Referee:Prof. Dr. Michael Thumm
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Abstract
English
Non-ischemic cardiomyopathies may be caused by genetic mutations but may also result from cytotoxic influences of chemotherapeutic drugs and the accumulation of misfolded proteins. Heat shock protein A4 (HSPA4) knockout mice have been shown to have muscular dystrophy, juvenile mortality and growth retardation, and concentric cardiac hypertrophy. Overexpression of HSPA4 has preserved a balance in protein quality control and avoided hypertrophic development of the left ventricle. The patchy histological pattern of fibrosis in mutant hearts suggests pauses in signal transmission, presumably due to gap junction disconnection. In the heart, it may be assumed that HSPA 4 is essential for preventing the aggregation of proteins and promoting degradation by the autophagic system. Additionally, mice treated with doxorubicin were protected from the proteotoxic side effects of this treatment by overexpressing HSPA4 in the heart, after which they were stressed with an acute lethal dose of the drug. Here the damaged proteins could be stabilized by increased HSP70:HSPA4 chaperoning efficiency and presumably chaperone-mediated autophagy. Chaperone-mediated autophagy is an HSPA70 and, therefore, also HSPA4 dependent process that encompasses lysosomal membrane integrity, acidification, and autophagic flux. If this process requires different nucleotide exchange and if HSP70:HSPA4 is involved has yet to be discovered. On the other hand, the DOX-induced mitochondrial damage and disrupted autophagic processes could lead to a metabolic imbalance in the cardiomyocytes, promoting a more fetal gene program initiating atrophic pathways that lead to cardiomyocyte “hibernation” The ATP-independent holdase abilities of HSPA4 could stabilize ROS-damaged mitochondrial proteins. In contrast, an increased autophagic clearance would provide an increased pool of amino acids that could be catabolized. Furthermore, excess HSPA4 protein pool did not lead to hyperactivation of protein degradation by either UPS or autophagic clearance in AAV9-HSPA4 treated control mice. This suggests excess could be therapeutic in reverse remodeling processes. The HSP70:HSPA4 chaperone-mediated autophagy could be beneficial in this context, and it would be interesting to investigate further the time-dependent proteostatic effect Autophagic degradation seems to have. It needs further research to supplement the insufficient protein pool with overexpression to improve cardiac function. Strengthening protein stability and autophagy could be advantageous as an adjuvant therapy to cardiotoxic chemotherapeutics like doxorubicin. Still, further experiments must be tested before drawing a conclusion if this holds. Ultimately, HSPA4 overexpression seemed to have beneficial effects on protein homeostasis in the heart, and gene therapeutic interventions might hold promising new prospects for the future.
Keywords: Heart Failure; Chemotherapy; Protein Quality Control; Gene Therapy