Eosinophils protect pressure overload- and β-adrenoreceptor agonist-induced cardiac hypertrophy

Aims Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. Methods and results A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and beta-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient Delta dblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. Delta dblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type (WT) mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In Delta dblGATA and WT mice, administration of ECP mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-beta signalling and fibrotic protein synthesis. The use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-beta signalling. Conclusion Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of ECPs in this human CVD.

Automated summary

This study explored the role of blood eosinophil counts and eosinophil cationic protein (ECP) levels in cardiac hypertrophy. It revealed positive correlations between blood eosinophil counts and left ventricular mass in humans. Further experiments in mice showed that eosinophil deficiency exacerbated cardiac hypertrophy and dysfunction. The study also demonstrated that repopulation of eosinophils from wild-type mice improved cardiac hypertrophy. Mechanistic studies revealed that eosinophil expression of IL4, IL13, and mEar1 were essential in controlling cardiomyocyte hypertrophy and death, as well as fibroblast TGF-beta signaling and fibrotic protein synthesis. The use of human cardiac cells yielded similar results. The study suggests a cardioprotective role for eosinophils and ECP in cardiac hypertrophy and highlights the therapeutic potential of ECPs in cardiovascular disease.