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Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons.
Dries, Eef; Santiago, Demetrio J; Gilbert, Guillaume; Lenaerts, Ilse; Vandenberk, Bert; Nagaraju, Chandan K; Johnson, Daniel M; Holemans, Patricia; Roderick, H Llewelyn; Macquaide, Niall; Claus, Piet; Sipido, Karin R.
Afiliação
  • Dries E; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Santiago DJ; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Gilbert G; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Lenaerts I; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Vandenberk B; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Nagaraju CK; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Johnson DM; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Holemans P; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Roderick HL; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Macquaide N; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Claus P; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
  • Sipido KR; Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat Leuven, Belgium.
Cardiovasc Res ; 114(11): 1512-1524, 2018 09 01.
Article em En | MEDLINE | ID: mdl-29668881
ABSTRACT

Aims:

In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling. We study myocytes from patients with end-stage HF, compared with non-failing (non-HF), and myocytes from pigs with MI and reduced left ventricular (LV) function, compared with sham intervention (SHAM). Methods and

results:

Single LV myocytes for functional studies were isolated according to standard protocols. Immunofluorescent staining visualized organization of TATS and RyRs. Ca2+ was measured by confocal imaging (fluo-4 as indicator) and using whole-cell patch-clamp (37°C). Spontaneous Ca2+ release events, Ca2+ sparks, as a readout for RyR activity were recorded during a 15 s period following conditioning stimulation at 2 Hz. Sparks were assigned to cell regions categorized as coupled or non-coupled sites according to a previously developed method. Human HF myocytes had more non-coupled sites and these had more spontaneous activity than in non-HF. Hyperactivity of these non-coupled RyRs was reduced by Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition. Myocytes from MI pigs had similar changes compared with SHAM controls as seen in human HF myocytes. As well as by CaMKII inhibition, in MI, the increased activity of non-coupled sites was inhibited by mitochondrial reactive oxygen species (mito-ROS) scavenging. Under adrenergic stimulation, Ca2+ waves were more frequent and originated at non-coupled sites, generating larger Na+/Ca2+ exchange currents in MI than in SHAM. Inhibition of CaMKII or mito-ROS scavenging reduced spontaneous Ca2+ waves, and improved excitation-contraction coupling.

Conclusions:

In HF and after MI, RyR microdomain re-organization enhances spontaneous Ca2+ release at non-coupled sites in a manner dependent on CaMKII activation and mito-ROS production. This specific modulation generates a substrate for arrhythmia that appears to be responsive to selective pharmacologic modulation.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arritmias Cardíacas / Canal de Liberação de Cálcio do Receptor de Rianodina / Sinalização do Cálcio / Miócitos Cardíacos / Insuficiência Cardíaca / Cardiomiopatias / Infarto do Miocárdio Tipo de estudo: Observational_studies / Prognostic_studies Limite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arritmias Cardíacas / Canal de Liberação de Cálcio do Receptor de Rianodina / Sinalização do Cálcio / Miócitos Cardíacos / Insuficiência Cardíaca / Cardiomiopatias / Infarto do Miocárdio Tipo de estudo: Observational_studies / Prognostic_studies Limite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2018 Tipo de documento: Article