Mitochondrial reprogramming induced by CaMKIIδ mediates hypertrophy decompensation

Circ Res. 2015 Feb 27;116(5):e28-39. doi: 10.1161/CIRCRESAHA.116.304682. Epub 2015 Jan 20.

Abstract

Rationale: Sustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation.

Objective: To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq.

Methods and results: Compared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion.

Conclusions: Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.

Keywords: G-protein; Gq; calcium-calmodulin-dependent protein kinase type 2; heart failure; mitochondrial uncoupling protein 3; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Apoptosis
  • Benzylamines / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / deficiency
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology*
  • Cardiomegaly / enzymology*
  • Cardiomegaly / physiopathology
  • Cardiomyopathy, Dilated / etiology*
  • Cardiomyopathy, Dilated / physiopathology
  • Cardiomyopathy, Dilated / prevention & control
  • Cells, Cultured
  • Disease Progression
  • GTP-Binding Protein alpha Subunits, Gq-G11 / deficiency
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / physiology
  • Gene Expression Profiling
  • Heart Failure / etiology*
  • Heart Failure / physiopathology
  • Ion Channels / biosynthesis
  • Ion Channels / genetics
  • Ion Channels / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria, Heart / physiology*
  • Mitochondrial Proteins / biosynthesis
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / physiology
  • Myocytes, Cardiac / metabolism
  • Oxidative Stress
  • PPAR alpha / biosynthesis
  • PPAR alpha / genetics
  • Point Mutation
  • Pressure
  • RNA Interference
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Rats
  • Reactive Oxygen Species
  • Sequence Analysis, RNA
  • Sulfonamides / pharmacology
  • Transfection
  • Uncoupling Protein 3

Substances

  • Benzylamines
  • Ion Channels
  • Mitochondrial Proteins
  • PPAR alpha
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Sulfonamides
  • Ucp3 protein, mouse
  • Ucp3 protein, rat
  • Uncoupling Protein 3
  • KN 93
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Acetylcysteine