Biology subjects

Loughrey, C. M.

Publications and source records attributed to Loughrey, C. M..

4 recordsLinked to original sources

bioRxiv2026

Identification of osteopontin as a positional and functional candidate gene for cardiac hypertrophy in the SHRSP rat

Left ventricular hypertrophy, common in cardiometabolic and renal disease, is a major risk factor for cardiovascular morbidity and mortality. Left ventricular mass is a highly heritable, polygenic trait. Linkage studies in WKY and SHRSP rats have identified a quantitative trait locus for left ventricular mass index on chromosome 14. Congenic strains, where trait-associated genetic loci are introduced into a control strain, can identify causal genetic mediators relevant to human disease. Chromosome 14 congenic (WKY.SPGla14a), WKY, and SHRSP strains underwent cardiac phenotyping and transcriptome profiling at; 1-3 days (neonate), 5 weeks, and 16-weeks. Compared to WKY, LVMI was significantly increased in SHRSP and WKY.SPGla14a at 5 weeks (LVMISHRSP-WKY=0.26g/kg, LVMIWKY.SPGla14a-WKY=0.30g/kg), prior to measured hypertension in this model. SHRSP blood pressure was significantly greater than WKY.SPGla14a, and WKY from 12-20 weeks (AUCdiff=497 vs WKY, AUCdiff=412 vs WKY.SPGla14a). Cardiac transcriptome analysis of neonate, 5-week, and 16-week hearts identified significantly increased expression of secreted phosphoprotein 1 (Spp1/osteopontin) in SHRSP and WKY.SPGla14a compared to WKY, which is positioned within the transferred congenic region. Overexpression of Spp1 mRNA significantly increased H9c2 cell size and was shown to be transferred in small extracellular vesicles (sEV). Overexpression of Spp1 in neonatal chromosome 14 congenic and SHRSP strains preceded development of increased cardiac mass and onset of hypertension. The congenic strategy identified Spp1 as a positional and functional candidate gene determining increased LVMI in the SHRSP model of human cardiovascular disease.

genetics↗

bioRxiv2025

Targeting Runx1 protects against heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a public health problem and an elusive illness for which there are few treatment options. HFpEF is a systemic condition with a broad phenotype including diastolic dysfunction, pulmonary oedema, exercise intolerance, and left ventricular (LV) hypertrophy, collectively resulting in enhanced morbidity and mortality. Master-regulator transcription factor RUNX1 has recently been identified as a mediator of pathological changes in many cardiac diseases, however its role in HFpEF was unknown. Here we show that inhibition of Runx1 limits adverse cardiac remodelling in a clinically relevant mouse model of HFpEF. Cardiomyocyte-specific tamoxifen-inducible Runx1-deficient mice with HFpEF are protected, with preservation of diastolic function, and attenuation of pulmonary oedema, exercise intolerance, and hypertrophy. Furthermore, targeting Runx1 in HFpEF by using gene transfer or small molecule inhibitors improves diastolic function, both in female and male mice. Overall, our research enhances our understanding of RUNX1 in cardiac disease and demonstrates a novel translational target for the treatment of HFpEF. Keywords: Heart failure with preserved ejection fraction, metabolic heart failure, diastolic dysfunction, hypertrophy, pulmonary oedema, exercise intolerance CLINICAL PERSPECTIVEHeart failure (HF) is a leading cause of death world-wide and traditionally divided into different subtypes according to cardiac ejection fraction (EF). In contrast to HF with reduced EF (HFrEF), there are limited treatment options for HF with preserved EF which is of considerable concern given that HFpEF is projected to become the dominant HF subtype in the future 1. RUNX1 has been demonstrated to play an important role in the development of many cardiac and non-cardiac diseases. As a result, the potential for RUNX1 inhibitors as therapeutic agents across various conditions has become increasingly evident. In this study we established the therapeutic potential of targeting RUNX1 in the context of HFpEF. Targeting RUNX1 in cardiomyocytes markedly attenuates the development of the HFpEF phenotype and therefore this novel translational therapeutic target has great potential to address one of the biggest challenges in cardiac research.

physiology↗

bioRxiv2025

Optimized protocols for commonly-used murine models of heart failure with preserved ejection fraction.

BackgroundHFpEF is a leading cause of death worldwide and clinically relevant preclinical models are required to identify new therapeutic targets. The most clinically representative murine models of heart failure with preserved ejection fraction (HFpEF) in common use include a "2-hit" model combining metabolic stress with hypertension (high-fat diet [HFD] + N(gamma)-nitro-L-arginine methyl ester [L-NAME]) and a "3-hit" model that includes age as an additional "hit" (age + HFD + deoxycorticosterone pivalate [DOCP]). However, both models have reproducibility challenges, and sub-strain and sex dependency. Here we optimize both preclinical models to overcome these challenges. MethodsIn this study we optimized both models: (1) The 2-hit model was optimised to reproduce HFpEF (defined as the induction and maintenance of obesity, hypertension, diastolic dysfunction, left ventricular hypertrophy, lung congestion, and exercise intolerance) in both C57BL/6N and 6J mice using increasing L-NAME doses (0.5 g/L to 1.75 g/L) and protocol lengths (7 weeks to 13 weeks); and (2) The 3-hit model used 12-week-old C57BL/6N and 6J mice and two aging protocols were compared: HFD for 7 months, or healthy chow for 5 months then high fat diet for 7 months. After HFD, mice received an intraperitoneal injection of DOCP to induce hypertension via sodium retention. To enhance and prolong the effect of DOCP, mice received 1% NaCl drinking water at the time of injection until sacrifice, henceforth called "4-hit". To ensure the phenotype was maintained, a second bolus of DOCP was administered 8 weeks after the first. ResultsFor the 2-hit protocol, HFpEF was successfully induced in C57BL/6J mice when exposed to a 13-week L-NAME protocol with gradually increasing dosage from 1.0 g/L to 1.75 g/L. C57BL/6N mice showed the desired parameters after 7-weeks of 0.5 g/L L-NAME, which were not augmented by increased dosage or time administered. For the 4-hit mice, after addition of 1% NaCl drinking water following DOCP administration, a clear HFpEF phenotype was observed in C57BL/6N and 6J mice in both male and females, and maintained for up to 12 weeks. ConclusionsOur modifications ensure the 2-hit model is equally effective in both commonly used J and N substrains of C57BL/6 mice. Our 4-hit model overcomes the challenges of the 3-hit model, enhances reproducibility and robustness, which we demonstrate across sexes and substrains. Both of these new protocols will enhance clinically relevant mechanistic studies on HFpEF.

physiology↗

bioRxiv2022

Inhibiting Runx1 protects heart function after myocardial infarction

Myocardial infarction is a major cause of death worldwide. Effective treatments are required that limit adverse cardiac remodelling and preserve cardiac contractility following myocardial infarction, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile myocardium bordering a newly created infarct is functionally distinct from the remote surviving myocardium; it is also a major determinant of adverse cardiac remodelling and whole heart contractility. Expression of the transcription factor RUNX1 is increased in the border zone at 1 day after myocardial infarction, suggesting potential for targeted therapeutic intervention. Here we demonstrate that RUNX1 drives reductions in cardiomyocyte contractility, sarcoplasmic reticulum-mediated calcium release, mitochondrial density, and the expression of genes important for oxidative phosphorylation. Antagonising RUNX1 expression via short-hairpin RNA interference preserved cardiac contractile function following myocardial infarction when delivered either via direct adenoviral delivery into the border zone or via an adeno-associated virus vector administered intravenously. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with the essential co-factor CBF{beta}. Both tamoxifen-inducible Runx1-deficient and Cbf{beta}-deficient cardiomyocyte-specific mouse models demonstrated that antagonising RUNX1 function preserves the expression of genes important for oxidative phosphorylation following myocardial infarction. Our results confirm the translational potential of RUNX1 as a novel therapeutic target in myocardial infarction, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.

pathology↗