title: Targeted disruption of Hspa4 gene leads to cardiac hypertrophy and fibrosis.
abstract: Failure of molecular chaperones to direct the correct folding of newly synthesized proteins leads to the accumulation of misfolded proteins in cells. HSPA4 is a member of the heat shock protein 110 family (HSP110) that acts as a nucleotide exchange factor of HSP70 chaperones. We found that the expression of HSPA4 is upregulated in murine hearts subjected to pressure overload and in failing human hearts. To investigate the cardiac function of HSPA4, Hspa4 knockout (KO) mice were generated and exhibited cardiac hypertrophy and fibrosis. Hspa4 KO hearts were characterized by a significant increase in heart weight/body weight ratio, elevated expression of hypertrophic and fibrotic gene markers, and concentric hypertrophy with preserved contractile function. In response to pressure overload, cardiac hypertrophy and remodeling were further aggravated in the Hspa4 KO compared to wild type (WT) mice. Cardiac hypertrophy in Hspa4 KO hearts was associated with enhanced activation of gp130-STAT3, CaMKII, and calcineurin-NFAT signaling. Protein blot and immunofluorescent analyses showed a significant accumulation of polyubiquitinated proteins in cardiac cells of Hspa4 KO mice. These results suggest that the myocardial remodeling of Hspa4 KO mice is due to accumulation of misfolded proteins resulting from impaired chaperone activity. Further analyses revealed a significant increase in cross sectional area of cardiomyocytes, and in expression levels of hypertrophic markers in cultured neonatal Hspa4 KO cardiomyocytes suggesting that the hypertrophy of mutant mice was a result of primary defects in cardiomyocytes. Gene expression profile in hearts of 3.5-week-old mice revealed a differentially expressed gene sets related to ion channels, muscle-specific contractile proteins and stress response. Taken together, our in vivo data demonstrate that Hspa4 gene ablation results in cardiac hypertrophy and fibrosis, possibly, through its role in protein quality control mechanism.
authors.affiliation: Institute of Human Genetics, University of Göttingen, Germany.
authors.forename: Belal A
authors.initials: BA
authors.lastname: Mohamed
authors.forename: Amal Z
authors.initials: AZ
authors.lastname: Barakat
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
authors.forename: Christian
authors.initials: C
authors.lastname: Mühlfeld
authors.forename: Mark
authors.initials: M
authors.lastname: Hünlich
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Engel
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Adham
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000235:genetics; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis; D005355:Fibrosis / Q000235:genetics; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D017510:Protein Folding; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics; D057149:Ubiquitinated Proteins / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D003285:Contractile Proteins; D050957:HSP110 Heat-Shock Proteins; C121993:HSPA4 protein, human; C485680:Hspa4 protein, mouse; D007473:Ion Channels; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D057149:Ubiquitinated Proteins; D050822:Cytokine Receptor gp130; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin