Abstract
Authors
Juliane Schwanbeck, Max Stahnke, Anna Eberlein, Madeleine Goeritzer, Arndt Schulze, Dominique Pernitsch, Dagmar Kolb, Gernot F. Grabner, Theda U.P. Bartolomaeus, Sofia K. Forslund, Holger Gerhardt, Gabriele G. Schiattarella, Lucia Cocera Ortega, Natalia López-Anguita, Erin E. Kershaw, Henrike Maatz, Norbert Hübner, Rudolf Zechner, Anna Foryst-Ludwig, Ulrich Kintscher
Figure 1
Endothelial deletion of ATGL protects against HFpEF.
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(A ) Representative IHC of aortas with ATGL (brown, marked by arrows) (top). Reduced expression (single nuclei RNA-Seq, LV) of Pnpla2 (Atgl) in ECs (n = 4; P < 0.001) (bottom). (B and C ) Body weight (BW) and systolic blood pressure (sBP) after 15 weeks. (D –J ) Echocardiographic parameters; Atglfl/fl-LFD (n = 7), ecAtglKO-LFD (n = 7), Atglfl/fl-HFpEF (n = 11), and ecAtglKO-HFpEF (n = 7) mice (2-way ANOVA with Bonferroni’s/Tukey’s multiple-comparison tests). Echocardiographic analysis of Atglfl/fl LFD (n = 7), ecAtglKO LFD (n = 7), Atglfl/fl HFpEF (n = 11), and ecAtglKO HFpEF (n = 7) mice (2-way ANOVA with Bonferroni’s multiple comparison tests). (D ) LV-ejection fraction (LVEF). (E –G ) Parameters of diastolic dysfunction: E/A, E/e’, IVRT. (H ) Representative pulse wave (top) and tissue Doppler (bottom) images. (I ) Representative B-Mode images with or without speckle-tracking algorithm. (J ) Global longitudinal strain (GLS). (K ) Representative transmission electron micrographs (TEM) from LVs (cyan asterisks indicate LDs in ECs; purple asterisks indicate LDs in cardiomyocytes [CM]). (L ) LD quantification shown as CM/EC ratio (2-way ANOVA/Bonferroni’s multiple comparison tests). (M ) Triacylglycerol (TAG) content of LVs (n = 4) (Wilcoxon test). (N –T ) Single nuclei RNA-Seq data from LV from Atglfl/fl and ecAtglKO mice (LFD/HFpEF, n = 4 per group). (N ) Global UMAP of all cell types present in LVs of Atglfl/fl-LFD/HFpEF and ecAtglKO-LFD/HFpEF mice. (O ) Volcano plot of differentially expressed genes (DEGs, P < 0.05; log2FC > 0.3). (P ) UMAP of the EC cluster. (Q ) Volcano plot of DEGs in capillary ECs (DEGs, P < 0.05; log2FC > 0.3). (R ) DEGs for lipid metabolism in CM (top), significant DEGs with P < 0.05 as dot plots (bottom) (Atglfl/fl-HFpEF versus ecAtglKO-HFpEF mice). (S ) DEGs characteristic for UPR in CMs: Atglfl/fl-LFD versus Atglfl/fl-HFpEF (left), Atglfl/fl-HFpEF versus ecAtglKO-HFpEF (right). (T ) GO term analysis of genes upregulated in cardiomyocytes from ecAtglKO-HFpEF versus Atglfl/fl-HFpEF mice. (U ) Graphical representation of study. *P < 0.05, ***P < 0.001, ****P < 0.0001.
