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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
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Genotype-Dependent and -Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy
Adam S Helms1, Francisco J Alvarado2, Jaime Yob2
1From Departments of Internal Medicine (A.S.H., J.Y., V.T.T., H.H.V., S.M.D.), Molecular and Integrative Physiology (F.J.A., H.H.V., S.M.D.), Cardiac Surgery (F.P.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor. adamhelm@med.umich.edu.
Circulation
|October 1, 2016
Summary
Aberrant calcium signaling in hypertrophic cardiomyopathy (HCM) involves distinct pathways. Sarcomere mutation-positive HCM shows CaMKII pathway activation, while all HCM reduces SERCA2A function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biochemistry
Background:
- Aberrant calcium signaling is implicated in hypertrophic cardiomyopathy (HCM) pathogenesis.
- Sarcomere gene mutations may uniquely disrupt cardiac calcium handling pathways.
Purpose of the Study:
- To investigate calcium regulatory pathway alterations in human HCM.
- To differentiate pathway changes based on sarcomere mutation status.
Main Methods:
- Analysis of gene expression, protein levels, and functional assays in human HCM samples (n=35) versus controls (n=8).
- Focus on key calcium handling proteins including SERCA2A, phospholamban, and CaMKII.
- Assessment of calcineurin and ryanodine receptor pathways.
Main Results:
- CaMKII (calcium/calmodulin-dependent protein kinase type II) pathway activation, specifically increased pT17-phospholamban, occurred only in sarcomere-mutation HCM.
- SERCA2A (sarcoplasmic endoplasmic reticular calcium ATPase 2) expression and function were reduced in all HCM cases, irrespective of genotype.
- No significant alterations were found in calcineurin or cardiac ryanodine receptor pathways.
Conclusions:
- HCM exhibits calcium mishandling via both common and genotype-specific mechanisms.
- Post-translational CaMKII activation is a hallmark of sarcomere mutation-positive HCM.
- Reduced SERCA2A function and sarcoplasmic reticulum calcium uptake are characteristic of HCM overall.
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