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Comprehensive bioinformatic analysis identifies potential therapeutic drugs for CryAB (R120G)-related cardiomyopathy
Jiaqi Zheng1,2, Yuyang Liu3, Jie Wang2
1Institute of Medical Technology, Peking University Health Science Center, Beijing, China.
Abstract:
CryAB, known as Alpha-B Crystallin, has also been shown to bind and increase the unfolding force of the filamentous protein. Mutation of CryAB at R120G causes serious cardiomyopathy but lacks ideal therapeutic drugs. In the present study, we constructed CryAB (R120G)-transgenic (TG) mice. One hundred and four differentially expressed genes (DEGs) in heart tissues of TG mice were screened through RNA sequencing. Gene ontology (GO) and KEGG pathway analyses highlighted enrichment in critical biological processes such as blood circulation regulation, contractile fiber formation, actin binding, thyroid hormone signaling, endocytosis, and alanine, aspartate, and glutamate metabolism. Protein-protein interaction (PPI) analysis pinpointed key hub genes, including DHTKD1, NKTR, SCN5A, CLCN1, RPA1, ACSF2, ACACB, TTC28, HSPA1B. By using Connectivity Map (CMap) analysis and transcriptome data, we identified phosphodiesterase (PDE) family as potential targets and several potential therapeutic candidates, with nortriptyline, torin-1, and cilostazol emerging as top candidates. Molecular docking simulations showed that Nortriptyline exhibited strong binding affinities with hub proteins, particularly SCN5A. These findings suggest promising new therapeutic strategies for CryAB(R120G)-related cardiomyopathy by targeting specific pathways and hub genes to mitigate cardiac dysfunction.
Insights
Alpha-B Crystallin (CryAB) mutation causes cardiomyopathy. Researchers identified key genes and pathways, finding phosphodiesterase (PDE) inhibitors like nortriptyline as potential treatments to mitigate cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Pharmacology
Background:
- Alpha-B Crystallin (CryAB) R120G mutation is linked to severe cardiomyopathy.
- Current therapeutic options for this condition are limited.
Purpose of the Study:
- To investigate the molecular mechanisms underlying CryAB(R120G)-induced cardiomyopathy.
- To identify potential therapeutic targets and drug candidates.
Main Methods:
- RNA sequencing to identify differentially expressed genes (DEGs) in CryAB(R120G)-transgenic mice.
- Gene Ontology (GO) and KEGG pathway analyses for biological process enrichment.
- Protein-protein interaction (PPI) network analysis to pinpoint hub genes.
- Connectivity Map (CMap) analysis and molecular docking simulations for drug discovery.
Main Results:
- Identified 104 DEGs and enriched pathways including blood circulation, contractile fiber formation, and metabolism.
- Pinpointed key hub genes such as DHTKD1, NKTR, and SCN5A.
- Identified phosphodiesterase (PDE) family as a potential target and nortriptyline, torin-1, and cilostazol as candidate drugs.
- Nortriptyline showed strong binding affinity with SCN5A via molecular docking.
Conclusions:
- CryAB(R120G) mutation triggers significant molecular changes in the heart.
- Targeting specific pathways and hub genes, particularly PDE family members, offers a promising therapeutic strategy.
- Nortriptyline is a potential therapeutic candidate for mitigating cardiac dysfunction in CryAB(R120G)-related cardiomyopathy.
