Ventromedial Hypothalamus Activation Aggravates Hypertension Myocardial Remodeling Through the Sympathetic Nervous System

Figures

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  Figure 1. Experimental protocol and pharmacogenetics method. (A) Experimental protocol (n = 6 per group); (B) Schematic diagram and representative image showing virus injection and hM3D(Gq)-EGFP expression in the VMH at 3 weeks. The scale bar represents 100 μm. VMH, ventromedial hypothalamus; ECG, electrocardiogram; UCG, ultrasonic cardiogram; CNO, clozapine-N-oxide; 3V, the third ventricle.

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  Figure 2. The increase of FOS B expression and systolic blood pressure after VMH activation. (A) Representative images (5x and 20x) and quantification of Fos B expression in the VMH. The scale bar represents 200 μm and 50 μm. Values are presented as mean ± SEM (n = 5 per group); (B) SBP was measured at 1W, 3W, and 5W. Values are presented as mean ± SEM (n = 6 per group). VMH, ventromedial hypothalamus; SBP, systolic blood pressure; *p < 0.05, **p < 0.01; vs. sham group; #p < 0.05, ##p < 0.01 vs. HTN group.

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  Figure 3. VMH activation aggravated cardiac remodeling. (A) Representative histological staining images (the scale bar represents 20 μm), Masson staining images (the scale bar represents 50 μm), and TUNEL staining images (the scale bar represents 50 μm) of left ventricle. (B) Quantification of myocytes cross-sectional areas, peripheral fibrosis areas, interstitial fibrosis areas, and TUNEL positive cells. Values are presented as mean ± SEM (n = 6 per group). (C) The relative mRNA expression of ANP and BNP. Values are presented as mean ± SEM (n = 5 per group). ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide. *p < 0.05, **p < 0.01; vs. sham group; #p < 0.05, ##p < 0.01 vs. HTN group.

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  Figure 4. VMH activation increased sympathetic nervous system activity. (A–C) Spectral analysis of heart rate variability: LF, HF, and the ratio of LF/HF; (D) NE levels in serum. Values are presented as mean ± SEM (n = 6 per group). LF, low frequency (0.20–0.75 Hz); HF, high frequency (0.75–2.5 Hz); LF/HF, the LF/HF ratio; NE, norepinephrine. **p < 0.01; vs. sham group; #p < 0.05, ##p < 0.01 vs. HTN group.

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  Figure 5. The RNA-seq and qPCR analysis results. (A) Heatmap of expression genes between HTN and HTN+VMH activation group (n = 3 per group); (B) Number of up-regulated and down-regulated genes between HTN and HTN+VMH activation group (n = 3 per group); (C) KEGG pathway enrichment analysis between HTN and HTN+VMH activation group; (D) GO biological process analysis between HTN and HTN+VMH activation group; (E) The relative mRNA expression of HIF-1α, PPARα, and CPT-1 in sham group, HTN group, and HTN+VMH activation group. Values are presented as mean ± SEM (n = 4 per group). **p < 0.01; vs. sham group; ##p < 0.01 vs. HTN group.

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  Figure 6. Schematic summary of the effects of VMH activation in HTN hypertension model. Emotional stress caused VMH activation could increase sympathetic nervous system activity. Upregulated sympathetic activity might increase HIF-1α expression and reduced PPARα and CPT-1 expression, then aggravated cardiac remodeling.