A growing body of evidence shows that the heart secretes factors to maintain its performance and coordinate cellular activities in response to stress/ or injury. Collectively, we refer to these cardiac-secreted factors as cardiokines. The identification and study of cardiokines is significant because it will provide information about intertissue communication within the heart, and these secreted factors may serve useful therapeutic or diagnostic functions. Via high throughput transcript analyses, we identified the secreted glycoprotein Follistatin-like 1 (Fstl1), also referred to as TSC36 and FRP, as a novel cardiokine. We demonstrated that Fstl1 is markedly upregulated by cardiac stress including ischemia-reperfusion injury, pressure overload and permanent left anterior descending coronary artery (LAD) ligation. We recently showed that acute overexpression of Fstl1 will protect the heart from ischemia-reperfusion injury and will promote revascularization of ischemic hind limbs in murine models. However, the functional role of Fstl1 in post- myocardial infarction (MI) cardiac remodeling is unknown, nor is it known how Fstl1 production by different cell types in the heart influence the remodeling process. In collaborative efforts with clinical laboratories we have found that Fstl1 can be detected in human serum, and these levels are prognostic for clinical outcomes in patients with either acute coronary syndrome or heart failure. Our pilot work in experimental models show that Fstl1 induction occurs both in cardiac myocytes and macrophages recruited to the infarct, suggesting that Fstl1 is involved in cardiac myocyte-macrophage crosstalk that coordinates the wound healing response in heart failure. Here we will evaluate the relative contributions of myocyte- versus macrophage-derived Fstl1 in post-MI remodeling. We will also explore the regulatory mechanisms and significance of Fstl1-mediated GDF15 regulation, whose importance is underscored by clinical data showing that these two factors participate in a biomarker network. Finally, we will examine the role of Dip2a, a recentl identified Fstl1 receptor molecule, in mediating the cardioprotective actions of Fstl1 on the heart To assess the role of Fstl1 in these processes, we will employ novel conditional knockout and overexpression models that have been created for these studies.
We will investigate the role of cardiac myocyte-derived Fstl1 in post-MI heart failure using genetic models and investigate the role of macrophage-derived Fstl1 in post-MI heart failure using genetic models. We will also evaluate the Fstl1-GDF15 signaling axis and the functional role of GDF15 in mediating the cardioprotective actions of Fstl1. Finally, we will analyze the role of Dip2a, a Fstl1 receptor, in heart using conditional knockout mice.
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