The Influence of the LINC00961/SPAAR Locus Loss on Murine Development, Myocardial Dynamics, and Cardiac Response to Myocardial Infarction.

Ana-Mishel Spiroski,Marco Meloni,Ian R Mccracken,Andrew H Baker,Rachel Sanders,Mairi Brittan,Gillian A Gray,Adrian Thomson

doi:10.3390/ijms22020969

Abstract

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR (small regulatory polypeptide of amino acid response) locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess human cardiac cell SPAAR expression, we mined a publicly available scRNSeq dataset and confirmed LINC00961 locus expression and hypoxic response in a murine endothelial cell line. We investigated post-natal growth and development, basal cardiac function, the cardiac functional response, and tissue-specific response to myocardial infarction. To investigate the influence of the LINC00961/SPAAR locus on longitudinal growth, cardiac function, and response to myocardial infarction, we used a novel CRISPR/Cas9 locus knockout mouse line. Data mining suggested that SPAAR is predominantly expressed in human cardiac endothelial cells and fibroblasts, while murine LINC00961 expression is hypoxia-responsive in mouse endothelial cells. LINC00961–/– mice displayed a sex-specific delay in longitudinal growth and development, smaller left ventricular systolic and diastolic areas and volumes, and greater risk area following myocardial infarction compared with wildtype littermates. These data suggest the LINC00961/SPAAR locus contributes to cardiac endothelial cell and fibroblast function and hypoxic response, growth and development, and basal cardiovascular function in adulthood.

Highlights

Over 17 million deaths worldwide annually are due to cardiovascular diseases (CVD) [1].With no clinically utilised therapeutics available to reverse the disease process, management focuses on reducing risk factors that exacerbate the “silent symptoms” which contribute to ischaemic diseases of the heart and vasculature
We have previously reported that the LINC00961/small regulatory polypeptide of amino acid response (SPAAR) locus contributes to angiogenesis in the peripheral musculature, and here we have shown the potential for its influence on in vivo cardiovascular function and response to localised cardiac ischaemia
We have shown that the left ventricular risk area following an acute Myocardial infarction (MI) is greater in LINC00961–/– mice compared to wildtype littermates

Summary

Introduction

Over 17 million deaths worldwide annually are due to cardiovascular diseases (CVD) [1]. With no clinically utilised therapeutics available to reverse the disease process, management focuses on reducing risk factors that exacerbate the “silent symptoms” which contribute to ischaemic diseases of the heart and vasculature. Whilst an MI shortens a patient’s life expectancy by >16 years [2,3], greater acute survival rates increases the incidence of subsequent heart failure. In concert with higher worldwide life expectancies and burgeoning increases in CVD risk factors, the economic and social burden of disease is everincreasing.

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