Abstract
A new familial dilated cardiomyopathy (FDCM) was found related to mutations in BAG3 gene. MicroRNAs (miRNAs) represent new targets of FDCM, although no studies have assessed clinical association between Bcl2-associated athanogene 3 (BAG3)-related DCM and miRNAs. Here, we studied whether a clinical association between BAG3-related FDCM and circulating miRNAs may have diagnostic and prognostic value in a small cohort of familial related individuals carrying a BAG3 mutation (BAG3+) and/or diagnosed of dilated cardiomyopathy (DCM) (DCM+). The analysis of 1759 circulating miRNAs showed significant differences between BAG3+ and BAG3- individuals for miRNAs mir-3191-3p, 6769b-3p, 1249-ep, 154-5p, 6855-5p, and 182-5p, while comparisons between BAG3+/DCM+ versus BAG3+/DCM- were restricted to miRNAs mir-154-5p, 6885-5p, and 182-5p, showing significant correlation with systolic and diastolic blood pressure, A wave, left atrium length, and left atrium area. Additionally, when stratified by gender and age, miRNAs were statistically correlated with critical parameters, including left ventricle ejection fraction (LVEF) and ventricular diameter, in women and young men. Likewise, 56% of BAG3+/DCM+, significantly co-expressed mir-154-5p and mir-182-5p, and a slight 4% did not express such combination, suggesting that co-expression of mir-154-5p and mir-182-5p may potentially show diagnostic value. Further studies will require long-term follow-up, and validation in larger populations.
Highlights
Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart, skeletal muscle, and some types of cancers
The culprit genes underlying the pathogenesis of more than 50% of familial dilated cardiomyopathy (DCM) are still unknown
• The culprit genes underlying the pathogenesis of more than 50% of familial DCM are still unknown
Summary
Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart, skeletal muscle, and some types of cancers. BAG3 works as a co-chaperone wit Hsc-70 facilitating the removal of misfolded and degraded proteins, and inhibits apoptosis by interacting with Bcl and maintaining the structural integrity of the Z-disk in the muscle [1,2]. Functional studies revealed that some forms of familial dilated cardiomyopathies (FDCMs) are related to BAG3 mutations with impaired Z-disc assembly and sensitivity to stress-induced apoptosis [3] proposing that myofibrillar integrity under mechanical stress is maintained by the complex BAG3–Hsc, since Hsc regulates the chaperone-dependent E3 ligase CHIP [4,5]. The relevance of BAG3 in the etiology of dilated cardiomyopathy (DCM) arise from studies in which the levels of BAG3 in the heart of patients with advance heart failure were significantly reduced, suggesting that BAG3 may represent a critical component to prevent. We have recently identified a rare variant causative of FDCM, detecting a novel frameshift (p.H243Tfr*64) genetic variation in BAG3 that is segregating in all affected family members, and it correlates with a severe phenotype of DCM [8]
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