Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy
Open Access
- 18 July 2019
- Vol. 8 (7), 741
- https://doi.org/10.3390/cells8070741
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were (1) several key PQC players were more abundant in HCM compared to controls, (2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, (3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, (4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and (5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.Keywords
Funding Information
- Dutch Heart Foundation (CVON2014-40 DOSIS, CVON-STW2016-14728 AFFIP)
This publication has 109 references indexed in Scilit:
- A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathyEuropean Heart Journal, 2011
- Opposing Actions of Extracellular Signal-regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) in Regulating Microtubule Stabilization during Cardiac HypertrophyPublished by Elsevier BV ,2011
- Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathyJournal of Molecular and Cellular Cardiology, 2010
- Starvation-induced Hyperacetylation of Tubulin Is Required for the Stimulation of Autophagy by Nutrient DeprivationPublished by Elsevier BV ,2010
- Heart Failure–Associated Changes in RNA Splicing of Sarcomere GenesCirculation: Cardiovascular Genetics, 2010
- αB-Crystallin Suppresses Pressure Overload Cardiac HypertrophyCirculation Research, 2008
- Sex and Age Dimorphism of Myocardial Gene Expression in Nonischemic Human Heart FailureCirculation: Cardiovascular Genetics, 2008
- Protein quality control and degradation in cardiomyocytesJournal of Molecular and Cellular Cardiology, 2008
- Intracellular Protein Aggregation Is a Proximal Trigger of Cardiomyocyte AutophagyCirculation, 2008
- Missense meanderings in sequence space: a biophysical view of protein evolutionNature Reviews Genetics, 2005