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Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

ABSTRACT: Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes. Caveolin-3 (Cav-3), integrins and related membrane repair proteins can function as cardioprotective proteins. Expression of these proteins in anthracycline-induced heart failure has not been evaluated. We tested the hypothesis that daunorubicin alters cardioprotective protein expression in the heart. Rabbits were administered daunorubicin (3 mg/kg, IV) weekly, for three weeks or nine weeks. Nine weeks but not three weeks of daunorubicin resulted in progressive reduced left ventricular function. Cav-3 expression in the heart was unchanged at three weeks of daunorubicin and increased in nine week treated rabbits when compared to control hearts. Electron microscopy showed caveolae in the heart were increased and mitochondrial number and size were decreased after nine weeks of daunorubicin. Activated beta-1 (β1) integrin and the membrane repair protein MG53 were increased after nine weeks of daunorubicin vs. controls with no change at the three week time point. The results suggest a potential pathophysiological role for Cav3, integrins and membrane repair in daunorubicin-induced heart failure.

SUBMITTER: Ichikawa Y

PROVIDER: S-EPMC5428970 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

Ichikawa Yasuhiro Y Zemljic-Harpf Alice E AE Zhang Zheng Z McKirnan M Dan MD Manso Ana Maria AM Ross Robert S RS Hammond H Kirk HK Patel Hemal H HH Roth David M DM

PloS one 20170512 5

Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes. Caveolin-3 (Cav-3), integrins and related membrane repair proteins can function as cardioprotective proteins. Expression of these proteins in anthracycline-induced heart failure has not been evaluated. We tested th ...[more]

PMID: 28498861

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Project description:BackgroundCardiac contractility modulation (CCM) is non-excitatory electrical stimulation for improving cardiac function. This study aimed to evaluate the effects of CCM on autophagy and apoptosis of cardiac myocytes in a rabbit model of chronic heart failure (CHF) and explore its possible mechanism.MethodsThirty rabbits were randomised into the Sham, heart failure (HF) and CCM groups, and animals in all three groups were sacrificed after 16 weeks of ascending aortic constriction or sham surgery. The expression of autophagy associated protein LC3 was observed by immunofluorescence staining. With Western-blot measured the expression of Beclin1, P62, LC3B (II/I) and Bcl-2, ALDH2, Bax and Caspase-3 protein in myocardial tissue. The apoptosis rate and the apoptosis of myocardial cells was observed by flow cytometry and TUNEL method.Results1) In comparison to the Sham group, the expression of LC3 and Beclin1 was significantly increased, and the expression of p62 protein was decreased in the heart tissues of rabbits in the HF group. Compared with HF group, after CCM intervention, the expression of Beclin1 and LC3B proteins decreased, while the P62 protein increased, and the LC3B(II/I) ratio decreased (P<0.05). 2) The expression of Bcl-2, ALDH2 protein and Bcl-2 mRNA decreased compared with the Sham group (P<0.05), while the expression of Bax, Caspase-3 protein and mRNA was significantly increased (P<0.05). However, the expression of ALDH2 mRNA in the CCM group was not statistically significant. The expression of Bcl-2, ALDH2 protein and mRNA increased after CCM intervention, and the expression of Bax, Caspase-3 protein and mRNA decreased (P<0.05). 3) The apoptosis situation in the Sham group was similar to that of normal myocardium, compared with the Sham group, the number of apoptotic bodies increased, and the apoptosis percentage of cardiomyocytes increased significantly (P<0.05). After CCM intervention, the number of apoptotic bodies and the percentage of apoptosis decreased compared with the HF group (P<0.05).ConclusionsThe intervention of CCM has been shown to enhance both myocardial systolic and diastolic function in rabbits with CHF. The mechanism may be related to the inhibition of cardiomyocyte autophagy by regulating the expression levels of Beclin1, P62, and LC3B(II/I) in cardiomyocytes, as well as the reversal of cardiomyocyte apoptosis by regulating the expression levels of Bcl-2, ALDH2, Bax, and Caspase-3 in cardiomyocytes.

Project description:The metabolic changes that accompany changes in Cardiopulmonary testing (CPET) and heart failure biomarkers (HFbio) are not well known. We undertook metabolomic and lipidomic phenotyping of a cohort of heart failure (HF) patients and utilized Multiple Regression Analysis (MRA) to identify associations to CPET and HFBio test performance (peak oxygen consumption (Peak VO2), oxygen uptake efficiency slope (OUES), exercise duration, and minute ventilation-carbon dioxide production slope (VE/VCO2 slope), as well as the established HF biomarkers of inflammation C-reactive protein (CRP), beta-galactoside-binding protein (galectin-3), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)). A cohort of 49 patients with a left ventricular ejection fraction < 50%, predominantly males African American, presenting a high frequency of diabetes, hyperlipidemia, and hypertension were used in the study. MRA revealed that metabolic models for VE/VCO2 and Peak VO2 were the most fitted models, and the highest predictors' coefficients were from Acylcarnitine C18:2, palmitic acid, citric acid, asparagine, and 3-hydroxybutiric acid. Metabolic Pathway Analysis (MetPA) used predictors to identify the most relevant metabolic pathways associated to the study, aminoacyl-tRNA and amino acid biosynthesis, amino acid metabolism, nitrogen metabolism, pantothenate and CoA biosynthesis, sphingolipid and glycerolipid metabolism, fatty acid biosynthesis, glutathione metabolism, and pentose phosphate pathway (PPP). Metabolite Set Enrichment Analysis (MSEA) found associations of our findings with pre-existing biological knowledge from studies of human plasma metabolism as brain dysfunction and enzyme deficiencies associated with lactic acidosis. Our results indicate a profile of oxidative stress, lactic acidosis, and metabolic syndrome coupled with mitochondria dysfunction in patients with HF tests poor performance. The insights resulting from this study coincides with what has previously been discussed in existing literature thereby supporting the validity of our findings while at the same time characterizing the metabolic underpinning of CPET and HFBio.

Dataset Information

Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

Publications

Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

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