BACKGROUND: Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail. METHODS AND RESULTS: Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15; P<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6; P=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells. CONCLUSIONS: High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.
BACKGROUND: Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail. METHODS AND RESULTS: Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15; P<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6; P=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells. CONCLUSIONS: High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.
Authors: Sjoukje I Lok; Nicolaas de Jonge; Joyce van Kuik; Ankie J P van Geffen; Manon M H Huibers; Petra van der Weide; Erica Siera; Bjorn Winkens; Pieter A Doevendans; Roel A de Weger; Paula A da Costa Martins Journal: PLoS One Date: 2015-10-02 Impact factor: 3.240
Authors: S I Lok; D J Lok; P van der Weide; B Winkens; P W Bruggink-André de la Porte; P A Doevendans; R A de Weger; P van der Meer; N de Jonge Journal: Neth Heart J Date: 2014-09 Impact factor: 2.380
Authors: Rebecca Messmann; Alexander Dietl; Stefan Wagner; Oliver Domenig; Carsten Jungbauer; Andreas Luchner; Lars S Maier; Simon Schopka; Stephan Hirt; Christof Schmid; Christoph Birner Journal: Mol Cell Biochem Date: 2020-06-20 Impact factor: 3.842