Meteorin-like protects the heart during chronic pressure overload

Aim: Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation’s potential benefits. Following acute myocardial infarction, myeloid cells recruited to the infarct region secrete the growth factor meteorin-like (METRNL), which exerts angiogenic effects via the stem cell factor (SCF) receptor KIT on endothelial cells. Considering that myeloid cells accumulate in the myocardium during chronic pressure-overload and that myocardial angiogenesis helps preserve heart function during persistent afterload stress, we examined the role of METRNL in this setting.

Methods and Results: We subjected wild-type (WT) mice to transverse aortic constriction (TAC) surgery and found Metrnl and Kit mRNAs upregulated in the left ventricular (LV) myocardium (both peaking on day 7; Metrnl 1.8-fold; Kit, 2.4-fold vs. sham; n=5–7; P<0.05). Using RT-qPCR and scRNA-seq, we identified monocytes, macrophages, and neutrophils as the main Metrnl-expressing cell types and endothelial cells as the main Kit-expressing cells. Mean METRNL plasma concentrations were 35% higher in aortic stenosis patients (n=12) than in age-matched healthy control individuals (n=13; measured by ELISA). Metrnl deficient (knockout, KO) mice had higher mortality (8 out of 17 KO mice died vs. 1 out of 14 WT mice; P<0.05) and more severely reduced LV function 6 weeks after TAC (echocardiographic fractional area change, 12 ± 2 in KO vs. 19 ± 2% in WT; n=14–17; P<0.01). Reduced heart function was accompanied by defective angiogenesis in pressure-overloaded KO mice, that became evident already on day 7. Using c-kit(H2B-tdTomato/+) reporter mice, we found that Kit(+), but not Kit(–), capillaries failed to expand in pressure-overloaded KO animals. At 6 weeks, KO mice also had developed more severe LV interstitial fibrosis (Sirius red staining) than their WT littermates. In vitro, recombinant METRNL and SCF dose-dependently stimulated angiogenesis in human coronary artery endothelial cells (ECs) but did not affect collagen 1A1 mRNA expression or cell migration of unstimulated or transforming growth factor-beta (TGFb)-stimulated neonatal rat cardiac fibroblasts (FBs). Interestingly, fibrosis endpoints were significantly inhibited after treating FBs with conditioned supernatants collected from METRNL- or SCF-stimulated ECs. High-resolution mass spectrometry analysis of METRNL-, SCF-, or vascular endothelial growth factor A (VEGFA)-stimulated EC supernatants revealed that METRNL and SCF’s secretome signatures clustered together and were segregated from VEGFA’s signatures in principal component space. In this dataset, we are currently defining METRNL- and SCF-induced EC-derived anti-fibrotic factors.

Conclusion: The myeloid cell-derived growth factor METRNL protects the heart during chronic pressure overload. METRNL-mediated adaptation is related to direct angiogenic and, possibly indirect, anti-fibrotic effects. METRNL thus emerges as a novel beneficial trait of inflammation in heart failure.