Induced expression of heat shock protein A4 protects the heart from proteotoxic stress

S. Gersch (Göttingen)¹, D. Marques Rodrigues (Göttingen)¹, M. Elkenani (Göttingen)¹, E. Sadrach (Göttingen)¹, K. Annamalai (Göttingen)¹, X. Xu (Göttingen)¹, P. Avramopoulos (München)², S. Engelhardt (München)³, S. Lutz (Göttingen)⁴, G. Hasenfuß (Göttingen)¹, K. Toischer (Göttingen)¹, B. A. Mohamed (Göttingen)^1
1Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; ²Technical University of Munich Institute of Pharmacology and Toxicology München, Deutschland; ³Technische Universität München (TUM) Institut für Pharmakologie und Toxikologie München, Deutschland; ⁴Universitätsmedizin Göttingen Institut für Pharmakologie und Toxikologie Göttingen, Deutschland

Background
Disruption in protein quality control (PQC) with consecutive protein aggregation plays a substantial role in the development of heart failure. Enhancement of PQC via overexpression of heat shock proteins was previously reported to mediate a cardioprotective effect. Hspa4 deletion in knockout (KO) mice resulted in the development of maladaptive cardiac remodeling, which is primarily due to misfolded protein accumulation.
Objectives
To address whether increased Hspa4 expression in cardiomyocytes could improve the cardiac PQC and, if so, could avert pathological cardiac remodeling.
Methods
In vitro siRNA-induced knockdown and adenoviral-mediated overexpression of Hspa4 were established. In vivo AAV9-induced Hspa4 expression in cardiomyocytes in 2 proteotoxicity mouse models, namely the Hspa4-KO mouse itself and doxorubicin (Dox)-induced cardiotoxicity, was carried out.
Results
Hspa4-KO mice developed diastolic dysfunction with premature cardiac mortality associated with compensatory activation of autophagy in the Hspa4-KO hearts. In vitro knockdown and overexpression resulted in aggravation and attenuation of hypertrophic cardiomyocyte response associated with increased and decreased accumulation of polyubiquitinated protein aggregates, respectively. Forced Hspa4 expression improved cardiac protein folding machinery and hence efficiently attenuated proteotoxicity-induced pathological cardiac remodeling in both Hspa4-KO and Dox-mouse model.
Conclusions
This study highlights the importance of improving PQC via induced cardiomyocyte Hspa4-expression, which may serve as a complementary therapeutic target for heart failure.