The heat shock proteins A4 (HSPA4) ameliorates pathological myocardial remodeling through improving protein homeostasis
Final Report Abstract
Emerging evidences suggest that misfolded protein aggregates play a crucial role in the development of cardiomyopathy. We have previously demonstrated that Hspa4 deletion results in accumulation of misfolded protein aggregates, leading to concentric cardiac hypertrophy and fibrosis. Here, we show that Hspa4-KO mice exhibit diastolic dysfunction and increased cardiac mortality with compensatory activation of autophagy in the heart. Interestingly, this pathological cardiac phenotype could be reversed upon forced Hspa4 re-expression associated with restoration of PQC. Additionally, augmenting Hspa4 expression efficiently enhanced the PQC in doxorubicin-treated mice, thereby reducing doxorubicin-induced cardiotoxicity. This study highlights the therapeutic relevance of induced Hspa4 expression against cardiac proteotoxic stress. Therefore, improving the capacity of the protein folding machinery via forced Hspa4 expression may serve as a complementary therapeutic strategy for HF, especially in HFpEF and doxorubicin-treated patients. Furthermore, our study demonstrated that HSPA4 overexpression attenuates proteotoxicity and enhances protein homeostasis in mice with PO-induced pathological cardiac remodeling. However, HSPA4 overexpression did not translate into beneficial effect on cardiac structure and function post-TAC with no improvement in survival. Further investigations are needed to elucidate the underlying mechanisms and identify potential therapeutic targets that can address both proteotoxicity and functional impairments in cardiac remodeling. Noteworthy, we demonstrated that the deletion of HSPA4 leads to a progressive generalized myopathy, highlighting the critical role of HSPA4 in regulating the genetic repertoire required for the appropriate maintenance of skeletal muscle integrity. Furthermore, these findings support the investigation of HSPA4 as a novel therapeutic target for the amelioration of many inherited muscle diseases with impaired autophagy. Although Hspa4 mutations have not yet been linked to any muscle morbidities in human, it remains to be addressed whether (cardio)myopathy patients with genetically unknown cause carry Hspa4 mutations. We therefore propose that genetic screening by Hspa4 gene sequencing could identify novel mutations and expand the spectrum of (cardio)myopathy-associated genes in patients with inherited muscle myopathies and/or cardiomyopathies.
Publications
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Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis. Journal of Translational Medicine, 20(1).
Elkenani, Manar; Barakat, Amal Z.; Held, Torsten; Rodrigues, Daniel Marques; Mobarak, Sherok; Swarnka, Surabhi; Adham, Ibrahim M. & Mohamed, Belal A.
