Abstract P3015: Cite-seq Identifies A Novel Role For Macrophage Trem2 In A Murine Model Of Hfpef
| Autor: | Charles Smart, Daniel Fehrenbach, Jean J Wassenaar, Vineet Agrawal, Anna R Hemnes, Amanda C Doran, Meena Madhur |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Circulation Research. 131 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Deoxycorticosterone acetate (DOCA)-salt is a common model of hypertension and has been used to study heart failure with preserved ejection fraction (HFpEF) in rats. Our goal was to validate DOCA-salt as a mouse model of HFpEF and to identify immune mediators of cardiac remodeling using unbiased methods. DOCA-salt mice underwent uninephrectomy, implantation of a DOCA pellet, and supplementation of the drinking water with 1%NaCl for three weeks. Control mice underwent a sham procedure and received normal water. Compared to control mice, DOCA-salt mice exhibited increased systolic blood pressure, cardiac hypertrophy, and decreased time to exhaustion upon treadmill exercise testing. In addition, DOCA-salt mice exhibited albuminuria, indicative of renal glomerular injury. On echocardiography, DOCA-salt mice exhibited a preserved ejection fraction. Invasive hemodynamic studies revealed an increased tau constant (5.70±.24, 8.22±.45; n=8,5) in DOCA-salt mice, consistent with diastolic dysfunction. CITE-seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, was performed on a total of 4,359 and 7,600 sorted leukocytes from four sham and four DOCA-salt left ventricles, respectively. Differential gene expression analysis revealed major transcriptional changes in cardiac macrophages between groups and identified Trem2 as being upregulated in cardiac macrophages. We validated a two-fold increase in Trem2 gene expression in left ventricles of DOCA-salt mice and observed a two-fold increase in cardiac Trem2+Mac2+ cells in DOCA-salt by immunofluorescence. To test whether Trem2 has a causal role in HFpEF, wild type and Trem2 deficient animals were subjected to DOCA-salt. After DOCA-salt, Trem2-deficient mice displayed significantly increased heart weight to tibia length ratios (9.39±0.20, 11.21±0.80; n=6-7) and albumin to creatinine ratios (5.5±1.2, 14.2±2.9; n=6-7) compared to wild-type controls. No difference in albuminuria was observed at baseline (0.36±0.05, 0.46±0.10; n=10). In conclusion, the DOCA-salt mouse model induces key features of HFpEF and identifies Trem2 as a potential novel modulator of cardiac remodeling and renal injury. |
| Databáze: | OpenAIRE |
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