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Optimized Protocol for the Extraction of Proteins from the Human Mitral Valve
Published on: June 14, 2017
The atrial and ventricular myocardial proteome of end-stage lamin heart disease
Constantin-Cristian Topriceanu1,2,3, Mashael Alfarih1,2, Alun D Hughes1,2
1UCL MRC Unit for Lifelong Health and Ageing, University College London, London, UK.
Insights
End-stage lamin heart disease, caused by the LMNA gene, affects the atria more than ventricles. This proteomics study found distinct protein changes, including increased lamin B and CA3, suggesting compensatory mechanisms.
Area of Science:
- Cardiovascular Proteomics
- Genetic Cardiology
- Molecular Medicine
Background:
- Dilated cardiomyopathy (DCM) can arise from mutations in the Lamin A/C (LMNA) gene.
- Understanding the molecular differences in end-stage lamin heart disease is crucial for targeted therapies.
Purpose of the Study:
- To investigate the post-genomic proteomic differences between end-stage lamin heart disease (LMNA-group) and ischemic DCM (ICM-group).
- To identify specific protein alterations in various heart tissues affected by LMNA gene mutations.
Main Methods:
- Prospective enrollment of patients undergoing heart transplantation (n=7 LMNA, n=7 ICM).
- Proteomic analysis using a discovery 'shotgun' proteomics approach on left atrium, left ventricle, right atrium, right ventricle, and interventricular septum samples.
- Comparative analysis of protein abundance between LMNA and ICM groups.
Main Results:
- 990 proteins were differentially abundant between LMNA and ICM groups, with the left atrium showing the most significant perturbation.
- Reduced lamin A/C and increased lamin B in LMNA atrial tissues; increased carbonic anhydrase 3 (CA3) and transthyretin across LMNA tissues.
- Sarcopenia, extracellular matrix remodeling, impaired myocardial energetics, redox imbalances, and abnormal calcium handling were identified in LMNA samples.
Conclusions:
- End-stage lamin heart disease is a biventricular and particularly biatrial disease.
- Increased lamin B, CA3, and transthyretin in LMNA hearts may represent compensatory responses.
- Proteomic profiling reveals key molecular pathways affected in LMNA-associated cardiomyopathy.
Abstract:
Lamins A/C (encoded by LMNA gene) can lead to dilated cardiomyopathy (DCM). This pilot study sought to explore the postgenomic phenotype of end-stage lamin heart disease. Consecutive patients with end-stage lamin heart disease (LMNA-group, n = 7) and ischaemic DCM (ICM-group, n = 7) undergoing heart transplantation were prospectively enrolled. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS), avoiding the infarcted myocardial segments in the ICM-group. Samples were analysed using a discovery 'shotgun' proteomics approach. We found that 990 proteins were differentially abundant between LMNA and ICM samples with the LA being most perturbed (16-fold more than the LV). Abundance of lamin A/C protein was reduced, but lamin B increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Carbonic anhydrase 3 (CA3) was over-abundant across all LMNA tissue samples (LA, LV, RA, RV, and IVS) when compared to ICM. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM, while sarcomeric proteins such as titin and cardiac alpha-cardiac myosin heavy chain were generally less abundant in RA/LA of LMNA. Protein expression profiling and enrichment analysis pointed towards sarcopenia, extracellular matrix remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Compared to ICM, end-stage lamin heart disease is a biventricular but especially a biatrial disease appearing to have an abundance of lamin B, CA3 and transthyretin, potentially hinting to compensatory responses.
