Post-transcriptional Regulation of α-1-Antichymotrypsin by MicroRNA-137 in Chronic Heart Failure and Mechanical Support

Abstract

There is substantial interest in applying proteomics to obtain better understanding of disease processes and to develop new biomarkers for diagnosis and early detection of cardiovascular diseases. 5,6 The purpose of the present study was to investigate proteomic changes in reverse remodeling during LVAD support. Because the degree of reverse remodeling is more pronounced in patients with nonischemic dilated cardiomyopathy (DCM), 7 we focused on this subset of patients. Recently, we found that levels of α-1-antichymotrypsin (ACT) expression decrease in myocardial tissue during pulsatile-LVAD support, which was detected by proteomics and confirmed by immunosorbent assays. 8 However, the molecular pathways regulating ACT expression in the heart were not explored.Clinically, pulsatile-LVAD support is being replaced by continuous-flow LVAD (cf-LVAD) support. Therefore, we performed proteomics in plasma and heart tissue of DCM Correspondence to Sjoukje Irene Lok, MD, University Medical Center Utrecht, Department of Cardiology, Huispostnummer H04.312, Postbus 85500, 3508 GA Utrecht, The Netherlands. E-mail s.lok@umcutrecht.nl 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. Delineating the role of miRs in post-transcriptional gene regulation offers new insight into the mechanisms by which the heart adapts to mechanical suppo...

Plasma levels of alpha-1-antichymotrypsin are elevated in patients with chronic heart failure, but are of limited prognostic value

“…Consequently, novel biomarkers are currently under intensive investigation and may be of help to improve the prognostication and clinical outcome of HF patients. Recently, we proposed a role of the acute-phase protein alpha-1-antichymotrypsin (ACT; also known as SERPINA3) in reverse remodelling [10]. Our previous data demonstrated that high ACT plasma and myocardial levels in HF decrease during mechanical support.…”

MicroRNA Expression in Myocardial Tissue and Plasma of Patients with End-Stage Heart Failure during LVAD Support: Comparison of Continuous and Pulsatile Devices

“…In agreement, our results show a significant increase in miR-378 and miR-378* in post pf-LVAD, indicating that increased expression levels of these miRs contribute to better cardiac function and therefore positive cardiac remodeling. Furthermore, we have very recently shown that miR-137 is implicated in reverse remodeling during cf-LVAD support by directly regulating alpha-1-antichymotrypsin, a potential new biomarker of HF [ 25 ].…”

“…MicroRNAs (miRs) are small, non-coding RNAs that bind mRNAs at their 3’-untranslated regions, stimulating mRNA degradation or inhibiting protein translation [ 22 ]. MiRs are important hallmarks for recovery or deterioration and might be used as a therapeutic target in HF [ 23 – 25 ]. Therefore, delineating their role in posttranscriptional gene regulation offers new insight into the mechanisms how the heart adapts to mechanical support.…”

Epigenetic Regulation in Heart Failure

“…Overexpression reduced interstitial fibrosis and heart failure in postmyocardial infarction rats miR-133 63 Collagen type 1 alpha 1 mRNA In Ang II dependent hypertension in rats, downregulation of miR-133 increases collagen type I alpha 1 production by myocytes in mice miR-137 64 Alpha-1-antichymotrypsin (ACT) miR-137 expression varied inversely with ACT mRNA in human cardiomyocytes and stromal cells miR-212/132 family 65 Fox03 transcription factor (antihypertrophic via calcineurin signaling suppression, also pro-autophagic via atrogin-1)…”