Dataset Information

Heart failure-inducible gene therapy targeting protein phosphatase 1 prevents progressive left ventricular remodeling.

ABSTRACT: BACKGROUND: The targeting of Ca(2+) cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum (SR) Ca(2+) ATPase, or ablation of phospholamban (PLN) and associated protein phosphatase 1 (PP1) protein complexes. We previously reported that PP1?, one of the PP1 catalytic subunits, predominantly suppresses Ca(2+) uptake in the SR among the three PP1 isoforms, thereby contributing to Ca(2+) downregulation in failing hearts. In the present study, we investigated whether heart-failure-inducible PP1?-inhibition by adeno-associated viral-9 (AAV9) vector mediated gene therapy is beneficial for preventing disease progression in genetic cardiomyopathic mice. METHODS: We created an adeno-associated virus 9 (AAV9) vector encoding PP1? short-hairpin RNA (shRNA) or negative control (NC) shRNA. A heart failure inducible gene expression system was employed using the B-type natriuretic protein (BNP) promoter conjugated to emerald-green fluorescence protein (EmGFP) and the shRNA sequence. AAV9 vectors (AAV9-BNP-EmGFP-PP1?shRNA and AAV9-BNP-EmGFP-NCshRNA) were injected into the tail vein (2×10(11) GC/mouse) of muscle LIM protein deficient mice (MLPKO), followed by serial analysis of echocardiography, hemodynamic measurement, biochemical and histological analysis at 3 months. RESULTS: In the MLPKO mice, BNP promoter activity was shown to be increased by detecting both EmGFP expression and the induced reduction of PP1? by 25% in the myocardium. Inducible PP1?shRNA delivery preferentially ameliorated left ventricular diastolic function and mitigated adverse ventricular remodeling. PLN phosphorylation was significantly augmented in the AAV9-BNP-EmGFP-PP1?shRNA injected hearts compared with the AAV9-BNP-EmGFP-NCshRNA group. Furthermore, BNP production was reduced, and cardiac interstitial fibrosis was abrogated at 3 months. CONCLUSION: Heart failure-inducible molecular targeting of PP1? has potential as a novel therapeutic strategy for heart failure.

SUBMITTER: Miyazaki Y

PROVIDER: S-EPMC3338799 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heart failure-inducible gene therapy targeting protein phosphatase 1 prevents progressive left ventricular remodeling.

Miyazaki Yosuke Y Ikeda Yasuhiro Y Shiraishi Kozo K Fujimoto Shizuka N SN Aoyama Hidekazu H Yoshimura Koichi K Inui Makoto M Hoshijima Masahiko M Kasahara Hideko H Aoki Hiroki H Matsuzaki Masunori M

PloS one 20120427 4

<h4>Background</h4>The targeting of Ca(2+) cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum (SR) Ca(2+) ATPase, or ablation of phospholamban (PLN) and associated protein phosphatase 1 (PP1) protein complexes. We previously reported that PP1β, one of the PP1 catalytic subunits, predominantly suppresses Ca(2+) uptake in the SR among the three PP1 isoforms, thereby contributi ...[more]

PMID: 22558250

Similar Datasets

Project description:BackgroundBeneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gα(q)) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Gα(q) (Gα(q)-TG).Methodology/principal findingsNicorandil (6 mg/kg/day) or vehicle was chronically administered to Gα(q)-TG from 8 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic nicorandil administration prevented the severe reduction of left ventricular fractional shortening and inhibited ventricular interstitial fibrosis in Gα(q)-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated Gα(q)-TG but not in nicorandil-treated Gα(q)-TG. eNOS gene expression was also increased in nicorandil-treated Gα(q)-TG compared with vehicle-treated Gα(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated Gα(q)-TG but in none of 10 nicorandil-treated Gα(q)-TG. The QT interval was significantly shorter in nicorandil-treated Gα(q)-TG than vehicle-treated Gα(q)-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused Gα(q)-TG mouse hearts. Moreover, HMR1098, a blocker of cardiac sarcolemmal K(ATP) channels, significantly attenuated the shortening of MAP duration induced by nicorandil in the Gα(q)-TG heart.Conclusions/significanceThese findings suggest that nicorandil can prevent the development of HF and ventricular arrhythmia caused by the activation of GPCR signaling through the shortening of the QT interval, action potential duration, the normalization of SERCA2 gene expression. Nicorandil may also improve the impaired coronary circulation during HF.

Project description:Circulating microRNAs (miRNAs) have been proposed as potential biomarkers for left ventricular remodeling in postinfarction heart failure (HF). However, the diagnostic reproducibility of the use of circulating miRNAs may be affected by the temporal expression of miRNAs following myocardial infarction (MI). In the current study, using a MI-induced HF rat cohort (4-, 8-, and 12-week post-MI groups), we investigated the temporal expression of plasma miRNAs during the development of left ventricular remodeling. The plasma miRNA expression profile was obtained using miRNA sequencing. The expression of candidate miRNAs in plasma and tissues was examined with real-time PCR. Target genes of candidate miRNAs were predicted using a parallel miRNA-messenger RNA expression profiling approach. The value of plasma miRNAs as biomarkers for left ventricular remodeling was evaluated in patients with postinfarction HF (n = 32) and control patients with stable angina and without significant coronary lesions and HF (n = 16) with real-time PCR. Although the expression levels of miR-20a-5p, miR-340-5p, and let-7i-5p were temporally regulated in plasma, myocardium, and peripheral blood mononuclear cells, the expression levels of plasma miRNAs, especially miR-20a-5p, were associated with the development of left ventricular remodeling in the postinfarction HF rat cohort. The target genes of these 3 miRNAs were associated with the mechanistic target of rapamycin, nuclear factor-κB, tumour necrosis factor, apoptosis, and p53 signaling pathways. Additionally, the plasma levels of miR-20a-5p, miR-340-5p, and let-7i-5p were significantly increased in patients with postinfarction HF. However, only the expression levels of miR-20a-5p presented significant positive correlations with left ventricular internal end diastolic dimension and left ventricular end diastolic volume. In conclusion, the expression levels of plasma miR-20a-5p were significantly associated with the degree of left ventricular dilatation, and plasma miR-20a-5p may be a potential biomarker for postinfarction left ventricular remodeling.

Dataset Information

Heart failure-inducible gene therapy targeting protein phosphatase 1 prevents progressive left ventricular remodeling.

Publications

Heart failure-inducible gene therapy targeting protein phosphatase 1 prevents progressive left ventricular remodeling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets