Biology subjects

Dash, P. R.

Publications and source records attributed to Dash, P. R..

3 recordsLinked to original sources

bioRxiv2026

Epidermal growth factor (EGF) receptor family signalling in cardiomyocyte hypertrophy and heart failure

The epidermal growth factor receptor (EGFR) family network comprises 4 receptors (EGFR, ERBB2, ERBB3, ERBB4) and numerous ligands, and is dysregulated in many cancers. Since anti-cancer drugs that target these receptors are cardiotoxic for some patients, it is important to understand the network in cardiac cells. Data from the Human Protein Atlas established that EGFR family members and their ligands are differentially expressed in cardiac cell types. Ligand expression was altered in human failing hearts and may contribute to disease. These ligands stimulated extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt in rat cardiomyocytes but to different degrees. Afatinib (at a concentration to inhibit all EGF family receptors) was used to assess the role of the network in a mouse model of cardiac hypertrophy induced by angiotensin II (AngII). Echocardiography and segmental strain analysis demonstrated that afatinib reduced AngII-induced cardiac hypertrophy and caused cardiac dysfunction. This was associated with loss of cardiomyocyte hypertrophy, enhanced cardiac fibrosis, and reduced expression of Nrg1. NRG1 binds to ERBB4 in cardiomyocytes which homodimerizes or heterodimerises with ERBB2. The role of ERBB2 in the cardiomyocyte response to NRG1 compared with EGF was dissected using tucatinib (a selective ERBB2 inhibitor) and mRNA expression profiling. Most, but not necessarily all, of the response to NRG1 required ERBB2 signalling; most, but not all, of the response to EGF did not. Thus, the EGFR family network plays an important role in the heart. Understanding this network may identify therapeutic approaches to avoid cardiotoxicity associated with EGFR family anti-cancer drugs. Clinical perspectivesO_LIAnti-cancer drugs that target the epidermal growth factor receptor (EGFR) family are cardiotoxic for some patients; it is therefore important to understand the network in cardiac cells. C_LIO_LIThe EGFR family and their ligands are differentially expressed in cardiac cells with changes in ligand expression in heart failure; inhibition of all receptors in a mouse model of hypertrophy reduces cardiac hypertrophy and causes cardiac dysfunction with attenuation of cardiomyocyte hypertrophy and enhanced cardiac fibrosis and loss of neuregulin 1 (NRG1); in rat cardiomyocytes, NRG1 signalling to gene expression is largely mediated via ERBB2. C_LIO_LIThe EGFR family network plays an important role in the heart; understanding this network may identify therapeutic approaches to avoid cardiotoxicity associated with anti-cancer drugs targeted against it. C_LI

biochemistry↗

bioRxiv2025

The anti-cancer drug trametinib suppresses angiotensin-induced cardiac remodelling in mice but is detrimental to function

Aims. Echocardiography is used widely in preclinical mouse studies, but the emphasis remains the histological/pathological/biochemical changes in the myocardium. Analysis/reporting of cardiac function is generally limited, often relying on M-mode assessment of a single plane across the left ventricle. The aim was to determine if global/segmental endocardial speckle-tracking (strain) has greater potential to assess function by distinguishing between mouse lines and identifying regional effects of different drugs. Methods and results. Echocardiograms from male C57Bl/6J (commercially-available) or C57Bl/6(R) (bred in-house) mice treated with vehicle or angiotensin II (AngII; 0.8 mg/kg/d, 7 d) were analysed. Global strain demonstrated different degrees of hypertrophy induced by AngII in the different lines, and variation in function (e.g. stroke volume/cardiac output were reduced in C57Bl/6J mice only, with no effect on global longitudinal strain). For C57Bl/6J mice, segmental strain (radial/longitudinal peak displacement/velocity/strain/strain rate) and frame-to-frame analysis of radial/longitudinal displacement identified more significant effects of AngII in the basal/mid-regions of the left ventricle. Thus, speckle-tracking distinguished between responses in different mouse lines. The methodology was applied to studies of anti-cancer drugs that inhibit extracellular signal-regulated kinase 1/2 signalling. Dabrafenib and/or trametinib inhibited AngII-induced cardiac hypertrophy, but dabrafenib alone caused abnormalities in endocardial movement whilst, for trametinib with AngII, more abnormalities were detected than with AngII alone. For both, the dominant effect was in the basal/mid-regions of the left ventricle. Conclusion. Echocardiography in preclinical studies can be exploited using endocardial segmental strain for greater insight into how drugs affect cardiac function in different regions of the left ventricle.

physiology↗

bioRxiv2023

Striatin plays a major role in angiotensin II-induced cardiomyocyte and cardiac hypertrophy in mice in vivo.

The three striatins (STRN, STRN3, STRN4) form the core of STRiatin-Interacting Phosphatase and Kinase (STRIPAK) complexes. These place protein phosphatase 2A (PP2A) in proximity to protein kinases thereby restraining kinase activity and regulating key cellular processes. Our aim was to establish if striatins play a significant role in cardiac remodelling associated with cardiac hypertrophy and heart failure. All striatins were expressed in control human hearts, with upregulation of STRN and STRN3 in failing hearts. We used mice with global heterozygote gene deletion to assess the roles of STRN and STRN3 in cardiac remodelling induced by angiotensin II (AngII; 7 days). Using echocardiography, we detected no differences in baseline cardiac function or dimensions in STRN+/- or STRN3+/- male mice (8 weeks) compared with wild-type littermates. Heterozygous gene deletion did not affect cardiac function in mice treated with AngII, but the increase in left ventricle mass induced by AngII was inhibited in STRN+/- (but not STRN3+/-) mice. Histological staining indicated that cardiomyocyte hypertrophy was inhibited. To assess the role of STRN in cardiomyocytes, we converted the STRN knockout line for inducible cardiomyocyte-specific gene deletion. There was no effect of cardiomyocyte STRN knockout on cardiac function or dimensions, but the increase in left ventricle mass induced by AngII was inhibited. This resulted from inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. The data indicate that cardiomyocyte striatin is required for early remodelling of the heart by AngII and identify the striatin-based STRIPAK system as a signalling paradigm in the development of pathological cardiac hypertrophy. Clinical perspectivesO_LIBackground. Striatins form the core of STRiatin-Interacting Phosphatase And Kinase (STRIPAK) complexes that regulate crucial cellular processes such as those associated with heart failure. C_LIO_LISummary. The three striatins are expressed in human hearts, with upregulation of STRN and STRN3 in failing hearts, whilst studies in mice indicate that STRN is required in cardiomyocytes for early remodelling of the hypertensive heart. C_LIO_LIPotential significance of results to human health and disease. STRN-based STRIPAKs represent a novel signalling paradigm in the development of pathological cardiac hypertrophy, and modulating this system may provide therapeutic options for managing the cardiac effects of hypertensive heart disease. C_LI

physiology↗