Abstract

Sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and its inhibitory protein called phospholamban (PLN) are pivotal for Ca2+ handling in cardiomyocyte and are known that their expression level and activity were changed in the heart failure patients. To examine whether PLN inhibition can improve survival rate as well as cardiac function in heart failure, we performed PLN ablation in calsequestrin overexpressing (CSQ-Tg) mice, a severe heart failure model, using clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system. According this method, generation rate of PLN wild type mice (PLN copy >0.95) and PLN homozygous knockout (KO) mice (PLN copy <0.05) were 39.1% and 10.5%, respectively. While CSQ overexpression causes severe heart failure symptoms and premature death, a significant ameliorating effect on survival rate was observed in PLN homozygous KO/CSQ-Tg mice compared to PLN wild type/CSQ-Tg mice (median survival days are 55 and 50 days, respectively). Measurement of cardiac function with cardiac catheterization at the age of 5 weeks revealed that PLN ablation improved cardiac function in CSQ-Tg mice without affecting heart rate and blood pressure. Furthermore, increases in atrial and lung weight, an index of congestion, were significantly inhibited by PLN ablation. These results suggest that PLN deletion would be a promising approach to improve both mortality and cardiac function in the heart failure.

Highlights

  • Heart failure (HF) is the complicated clinical syndrome characterized by progressive cardiac remodeling and dysfunction

  • PLN inhibition and SERCA2a activation are known to show beneficial effects on cardiac function and hypertrophy in various HF models [17,18,19], and increase contractility in the cardiomyocytes isolated from heart failure patients [30], there are few reports with respect to improvement of HF mortality [28, 29]

  • PLN homozygous knockout showed a significant improvement of cardiac function in calsequestrin overexpressing (CSQ-Tg) mice as previously reported [17], it was thought that blood supply to whole body was doi:10.1371/journal.pone.0168486.g005

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Summary

Introduction

Heart failure (HF) is the complicated clinical syndrome characterized by progressive cardiac remodeling and dysfunction. Prevalence of HF is growing due to raise of aging population in the developed countries, more novel and effective treatments for HF is required. Improvement of Heart Failure Mortality by Phospholamban Ablation materials and compounds used in this study are commercially available. There are no patents and products in development or market products to declare. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials

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