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Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

ABSTRACT: The increasing burden of heart failure globally can be partly attributed to the increased prevalence of diabetes, and the subsequent development of a distinct form of heart failure known as diabetic cardiomyopathy. Despite this, effective treatment options have remained elusive, due partly to the lack of an experimental model that adequately mimics human disease. In the current study, we combined three consecutive daily injections of low-dose streptozotocin with high-fat diet, in order to recapitulate the long-term complications of diabetes, with a specific focus on the diabetic heart. At 26 weeks of diabetes, several metabolic changes were observed including elevated blood glucose, glycated haemoglobin, plasma insulin and plasma C-peptide. Further analysis of organs commonly affected by diabetes revealed diabetic nephropathy, underlined by renal functional and structural abnormalities, as well as progressive liver damage. In addition, this protocol led to robust left ventricular diastolic dysfunction at 26 weeks with preserved systolic function, a key characteristic of patients with type 2 diabetes-induced cardiomyopathy. These observations corresponded with cardiac structural changes, namely an increase in myocardial fibrosis, as well as activation of several cardiac signalling pathways previously implicated in disease progression. It is hoped that development of an appropriate model will help to understand some the pathophysiological mechanisms underlying the accelerated progression of diabetic complications, leading ultimately to more efficacious treatment options.

SUBMITTER: Tate M

PROVIDER: S-EPMC6868003 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

Tate Mitchel M Prakoso Darnel D Willis Andrew M AM Peng Cheng C Deo Minh M Qin Cheng Xue CX Walsh Jesse L JL Nash David M DM Cohen Charles D CD Rofe Alex K AK Sharma Arpeeta A Kiriazis Helen H Donner Daniel G DG De Haan Judy B JB Watson Anna M D AMD De Blasio Miles J MJ Ritchie Rebecca H RH

Frontiers in physiology 20191114

The increasing burden of heart failure globally can be partly attributed to the increased prevalence of diabetes, and the subsequent development of a distinct form of heart failure known as diabetic cardiomyopathy. Despite this, effective treatment options have remained elusive, due partly to the lack of an experimental model that adequately mimics human disease. In the current study, we combined three consecutive daily injections of low-dose streptozotocin with high-fat diet, in order to recapi ...[more]

PMID: 31798462

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Project description:Diabetic cardiomyopathy is characterized by diabetes-induced myocardial abnormalities, accompanied by inflammatory response and alterations in inflammation-related signalling pathways. Kirenol, isolated from Herba Siegesbeckiae, has potent anti-inflammatory properties. In this study, we aimed to investigate the cardioprotective effect of kirenol against DCM and underlying the potential mechanisms in a type 2 diabetes mellitus model. Kirenol treatment significantly decreased high glucose-induced cardiofibroblasts proliferation and increased the cardiomyocytes viability, prevented the loss of mitochondrial membrane potential and further attenuated cardiomyocytes apoptosis, accompanied by a reduction in apoptosis-related protein expression. Kirenol gavage could affect the expression of pro-inflammatory cytokines in a dose-dependent manner but not lower lipid profiles, and only decrease fasting plasma glucose, fasting plasma insulin and mean HbA1c levels in high-dose kirenol-treated group at some time-points. Left ventricular dysfunction, hypertrophy, fibrosis and cell apoptosis, as structural and functional abnormalities, were ameliorated by kirenol administration. Moreover, in diabetic hearts, oral kirenol significantly attenuated activation of mitogen-activated protein kinase subfamily and nuclear translocation of NF-κB and Smad2/3 and decreased phosphorylation of IκBα and both fibrosis-related and apoptosis-related proteins. In an Electrophoretic mobility shift assay, the binding activities of NF-κB, Smad3/4, SP1 and AP-1 in the nucleus of diabetic myocardium were significantly down-regulated by kirenol treatment. Additionally, high dose significantly enhanced myocardial Akt phosphorylation without intraperitoneal injection of insulin. Kirenol may have potent cardioprotective effects on treating for the established diabetic cardiomyopathy, which involves the inhibition of inflammation and fibrosis-related signalling pathways and is independent of lowering hyperglycaemia, hyperinsulinemia and lipid profiles.

Project description:BackgroundIn complex Metazoans a given gene frequently codes for multiple protein isoforms, through processes such as alternative splicing. Large scale functional annotation of these isoforms is a key challenge for functional genomics. This annotation gap is increasing with the large numbers of multi transcript genes being identified by technologies such as RNASeq. Furthermore attempts to characterise the functions of splicing in an organism are complicated by the difficulty in distinguishing functional isoforms from those produced by splicing errors or transcription noise. Tools to help prioritise candidate isoforms for testing are largely absent.ResultsIn this study we implement a Time-course Switch (TS) score for ranking isoforms by their likelihood of producing additional functions based on their developmental expression profiles, as reported by modENCODE. The TS score allows us to better investigate functional roles of different isoforms expressed in multi transcript genes. From this analysis, we find that isoforms with high TS scores have sequence feature changes consistent with more deterministic splicing and functional changes and tend to gain domains or whole exons which could carry additional functions. Furthermore these functions appear to be particularly important for essential regulatory roles, establishing functional isoform switching as key for regulatory processes. Based on the TS score we develop a Transcript Annotations Pipeline for Alternative Splicing (TAPAS) that identifies functional neighbourhoods of potentially interesting isoforms.ConclusionsWe have identified a subset of protein isoforms which appear to have high functional significance, particularly in regulation. This has been made possible through the development of novel methods that make use of transcript expression profiles. The methods and analyses we present here represent important first steps in the development of tools to address the near complete lack of isoform specific function annotation. In turn the tools allow us to better characterise the regulatory functions of alternative splicing in more detail.

Dataset Information

Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

Publications

Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

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