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Global expression profiling identifies a novel biosignature for protein aggregation R120GCryAB cardiomyopathy in mice
Namakkal S Rajasekaran1, Matthew A Firpo, Brett A Milash
1Departments of Internal Medicine, Division of Cardiology, Center for Cardiovascular Translational Biomedicine, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Insights
Protein aggregation cardiomyopathy is linked to reductive stress from a specific gene mutation. Glutathione pathway gene expression changes serve as an early biosignature for predicting disease onset and progression.
Area of Science:
- Cardiovascular Medicine
- Molecular Biology
- Genetics
Background:
- Protein aggregation cardiomyopathy arises from mutations in the alphaB-crystallin gene (hR120GCryAB).
- Previous studies linked cardiac hR120GCryAB expression to increased glucose 6-phosphate dehydrogenase (G6PD) activity and reductive stress in mice.
- The initial molecular events driving this toxic gain-of-function remain unclear.
Purpose of the Study:
- To identify a biosignature for predicting the onset, progression, and outcome of hR120GCryAB cardiomyopathy.
- To elucidate the molecular pathogenesis of this condition.
Main Methods:
- Integrated systems approach utilizing gene expression profiling in transgenic mouse hearts.
- Comparison of gene expression in hR120GCryAB transgenic mice, wild-type hCryAB transgenic mice, and non-transgenic controls at different disease stages (3 and 6 months).
Main Results:
- At 3 months, upregulated pathways included stress response, glutathione metabolism, and complement/coagulation cascades.
- At 6 months, ribosomal synthesis and cellular remodeling pathways were also upregulated, alongside cardiac hypertrophy.
- Downregulated pathways involved oxidative phosphorylation, fatty acid metabolism, and energy balance, supporting the role of reductive stress in decompensation.
Conclusions:
- Reductive stress is a confirmed causal mechanism in hR120GCryAB cardiomyopathy.
- Alterations in glutathione pathway gene expression represent an early biosignature for presymptomatic detection of this cardiomyopathy.
Abstract:
Protein aggregation cardiomyopathy is a life-threatening manifestation of a multisystem disorder caused by the exchange mutation in the gene encoding the human small heat shock protein alphaB-crystallin (hR120GCryAB). Genetic studies in mice have established cardiac hR120GCryAB expression causes increased activity of glucose 6-phosphate dehydrogenase (G6PD) and "reductive stress" (Rajasekaran et al., Cell 130: 427-439, 2007). However, the initiating molecular events in the pathogenesis of this novel toxic gain-of-function mechanism remain poorly defined. In an integrated systems approach using gene expression profiling, we identified a "biosignature," whose features can be validated to predict the onset, rate of progression, and clinical outcome of R120GCryAB cardiomyopathy. At the 3 mo disease-related but compensated stage, we demonstrate that transcripts were only upregulated in three distinct pathways: stress response (e.g., Hsp70, Hsp90), glutathione metabolism (Gpx1, Gpx3, glutathione S-transferase), and complement and coagulation cascades in hR120GCryAB transgenic mouse hearts compared with either hCryAB WT transgenic mice or nontransgenic controls. In 6 mo old myopathic hearts, ribosomal synthesis and cellular remodeling associated with increased cardiac hypertrophy were additional upregulated pathways. In contrast, the predominant downregulated pathways were for oxidative phosphorylation, fatty acid metabolism, intermediate metabolism, and energetic balance, supporting their primary pathogenic roles by which G6PD-dependent reductive stress causes cardiac decompensation and overt heart failure in hR120GCryAB cardiomyopathy. This study extends and confirms our previous findings that reductive stress is a causal mechanism for hR120G CryAB cardiomyopathy and demonstrates that alteration in glutathione pathway gene expression is an early biosignature with utility for presymptomatic detection.
