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Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy

Larissa M Dorsch1, Maike Schuldt2, Cristobal G dos Remedios3

  • 1Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HV Amsterdam, The Netherlands. l.dorsch@vumc.nl.

Cells
|July 21, 2019
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) involves genetic mutations affecting sarcomere proteins. This study reveals that HCM disrupts the protein quality control (PQC) system and microtubule network in heart cells, offering new insights into disease mechanisms.

Area of Science:

  • Cardiovascular Genetics
  • Cellular Proteostasis
  • Inherited Cardiac Diseases

Background:

  • Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder.
  • Mutations in sarcomere protein genes are the primary cause of HCM.
  • Sarcomere protein mutations can disrupt cardiomyocyte protein quality control (PQC) and proteostasis.

Purpose of the Study:

  • To investigate HCM and mutation-specific alterations in cardiomyocyte PQC.
  • To compare PQC and microtubule network changes in HCM patients versus controls.
  • To identify novel pathomechanisms in HCM, particularly related to haploinsufficiency.

Main Methods:

  • Comparative analysis of left ventricular tissue from controls, sarcomere mutation-positive HCM (HCMSMP), and sarcomere mutation-negative HCM (HCMSMN) patients.
  • Quantification of key PQC players, heat shock proteins (HSPs), and α-tubulin/acetylated α-tubulin levels.
  • Correlation analysis between protein levels and clinical parameters.

Main Results:

  • Increased abundance of several key PQC players in HCM tissues.
  • Elevated levels of heat shock proteins (HSPB1, HSPD1, HSPA2) in HCMSMP compared to controls.
  • Higher levels of α-tubulin and acetylated α-tubulin in HCM, particularly in HCM with haploinsufficiency (HCMHI).
  • Inverse correlation between myosin-binding protein-C (cMyBP-C) and α-tubulin; correlation between α-tubulin, acetylated α-tubulin, and HSPs.

Conclusions:

  • Genetic mutations in HCM significantly impact the PQC system and α-tubulin acetylation.
  • Haploinsufficiency of cMyBP-C may initiate HSP responses and α-tubulin acetylation.
  • Microtubule network proliferation could be a novel pathomechanism in cMyBP-C haploinsufficiency-related HCM.

Keywords:
autophagycardiomyopathyhaploinsufficiencyheat shock proteinshypertrophymicrotubulespoison polypeptideprotein quality controlsarcomere mutation

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