Role of eosinophil cationic proteins in cardiac hypertrophy

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Coronary heart diseases remain the leading cause of deaths in the US. Despite the success of lipid lowering, residual risk remains. Current clinical studies support the participation of inflammation in cardiovascular diseases (CVD). Eosinophils (EOS) develop in the bone-marrow under the control of transcription factor GATA1. These granule cells accumulate in blood or at the site of inflammation. Blood EOS counts and EOS cationic protein (ECP) levels associate positively with the major CVD risk factors, prevalence, and mortality. Yet other studies reported reduced blood EOS counts and ECP levels in patients with major adverse cardiac events and heart failure (HF). Therefore, the role for EOS in human CVD remains unsettled. We reported that patients with hypertension showed positive association between blood EOS counts and hypertrophic measures. Using transverse aortic constriction (TAC)- and β-adrenergic receptor agonist isoproterenol (ISO)-induced cardiac hypertrophy and HF in EOS-deficient ∆dblGATA mice and in diphtheria toxin-induced EOS-depleted iPHIL mice, we demonstrated a reparative role of EOS in cardiac hypertrophy and HF by producing IL4 and cationic protein (mEar1). Mechanistic studies reported a role for EOS-derived IL4 and cationic proteins (mEar1, ECP) in blocking cardiomyocyte hypertrophy and apoptosis, and in inhibiting cardiac fibroblast TGF-β signaling and fibrosis. EOS granules contain cytokines, chemokines, growth factors, in addition to cationic proteins. To avoid ambitious concern, we will only study EOS cationic proteins in this proposal, as many other cells in hypertrophic heart also express these EOS cytokines, chemokines, and growth factors. Human EOS cationic protein ECP was identified 50 years ago and has been used as a biomarker for many human diseases, but it remains unknown whether and how ECP contributes to human diseases. Our preliminary studies showed that cardiomyocytes express bone morphogenetic protein receptor BMPR-1A and 1B, but not BMPR-2. In contrast, cardiac fibroblasts express BMPR-2 but not BMPR-1A or 1B. mEar1 uses BMPR-1A and 1B on cardiomyocytes as its receptor to activate the Smad-1/5/8 signaling and to block ISO-induced cardiomyocyte hypertrophy, but uses BMPR-2 on cardiac fibroblasts to block TGF-β-induced Smad2/3 signaling and fibrotic protein expression. In this proposal, we hypothesize that EOS protect heart from hypertrophy and HF by releasing cationic proteins to block cardiomyocyte hypertrophy and apoptosis and to inhibit cardiac fibroblast activation. EOS cationic proteins (mouse mEar1 and human ECP and EDN) exert their cardioprotective roles using BMPR-1A and 1B as their receptors on cardiomyocytes and BMPR-2 as their receptor on cardiac fibroblasts. Maintenance of functional receptors for EOS cationic proteins is essential to the cardioprotective role of human or mouse EOS. We propose two Aims to explore the molecular mechanisms by which EOS cationic proteins protect cardiomyocytes from hypertrophic injury and, to explore the molecular mechanisms by which EOS cationic proteins inhibit cardiac fibroblast fibrotic protein expression.