Abstract | BACKGROUND: Although the genetic causes of hypertrophic cardiomyopathy (HCM) are widely recognized, considerable lag in the development of targeted therapeutics has limited interventions to symptom palliation. This is in part attributable to an incomplete understanding of how point mutations trigger pathogenic remodeling. As a further complication, similar mutations within sarcomeric genes can result in differential disease severity, highlighting the need to understand the mechanism of progression at the molecular level. One pathway commonly linked to HCM progression is calcium homeostasis dysregulation, though how specific mutations disrupt calcium homeostasis remains unclear. METHODS: RESULTS: We measured an increase in phosphorylation of CaMKII in R92W animals by 6 months of age, indicating increased autonomous activity of the kinase in these animals. Inhibition of CaMKII led to recovery of diastolic function and partially blunted atrial remodeling in R92W mice. This improved function was coupled to increased sarcoplasmic reticulum Ca2+ATPase activity in the R92W animals despite reduction of CaMKII activation, likely indicating improvement in myocellular calcium handling. In contrast, inhibition of CaMKII in R92L animals led to worsened myocellular calcium handling, remodeling, and function. Diltiazem-HCl arrested diastolic dysfunction progression in R92W animals only, with no improvement in cardiac remodeling in either genotype. CONCLUSIONS: We propose a highly specific, mutation-dependent role of activated CaMKII in HCM progression and a precise therapeutic target for clinical management of HCM in selected cohorts. Moreover, the mutation-specific response elicited with diltiazem highlights the necessity to understand mutation-dependent progression at a molecular level to precisely intervene in disease progression.
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Authors | Sarah J Lehman, Lauren Tal-Grinspan, Melissa L Lynn, Joshua Strom, Grace E Benitez, Mark E Anderson, Jil C Tardiff |
Journal | Circulation
(Circulation)
Vol. 139
Issue 12
Pg. 1517-1529
(03 19 2019)
ISSN: 1524-4539 [Electronic] United States |
PMID | 30586744
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Calcium Channel Blockers
- Calcium-Binding Proteins
- Peptides
- Troponin T
- phospholamban
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
- Diltiazem
- Calcium
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Topics |
- Animals
- Atrial Remodeling
(drug effects)
- Calcium
(metabolism)
- Calcium Channel Blockers
(pharmacology, therapeutic use)
- Calcium-Binding Proteins
(metabolism)
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
(chemistry, metabolism)
- Cardiomyopathy, Hypertrophic
(drug therapy, genetics, pathology)
- Diltiazem
(pharmacology, therapeutic use)
- Disease Models, Animal
- Disease Progression
- Echocardiography
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Mutagenesis, Site-Directed
- Peptides
(pharmacology, therapeutic use)
- Phosphorylation
(drug effects)
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
(metabolism)
- Troponin T
(genetics, metabolism)
- Ventricular Function
(drug effects)
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