Sympathetic Nervous System Mediates Cardiac Remodeling After Myocardial Infarction in a Circadian Disruption Model

Figures

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  Figure 1. Cardiac function and structure were aggravated by circadian disruption after MI. Experimental protocol is outlined in (A). Representative images of echocardiography in all groups are shown in (B). (C–F) Differences of EF, FS, LVIDs, LVIDd among three groups. (G) Δweight (weight gain over the 30 days following MI). (H) Serum TG level. EF, ejection fraction; FS, fractional shortening; LVIDs, left ventricular internal dimension (systole); LVIDd, left ventricular internal dimension (diastole); TG, triglyceride; *p < 0.05.

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  Figure 2. Cardiac fibrosis and sympathetic remodeling were aggravated by circadian disruption after MI. Representative images of staining for Masson (blue) and α-SMA (red) in all groups are shown in (A), and quantitative analysis is shown in (B,C). Real-time PCR results of TGF-β1 are shown in (D). TH and SYN staining are used to assess sympathetic nerve sprouting and synaptic density in the heart (E–G). (H,I) Serum NE levels. α-SMA, alpha smooth muscle actin; TGF-β1, transforming growth factor beta 1; NE, norepinephrine; TH, tyrosine hydroxylase; SYN, synaptophysin; p* < 0.05.

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  Figure 3. Circadian disruption activated the “SCN-PVN-SCG-Heart” sympathetic axis. Retrograde tracer virus is injected into the ventricular myocardium in the apex region (A), and labeled neurons were identified in the heart (B), SCG (C), PVN (D), and SCN (E) regions. (F–K) Expression levels of c-fos at the SCN, PVN, and SCG sites. EGFP, enhanced green fluorescent protein; SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus of hypothalamus; SCG, superior cervical ganglion; p* < 0.05.

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  Figure 4. Sympathetic ganglionic blockade by DREADD. (A) Experimental protocol of DREADD. (B) Rationale of DREADD. (C) virus-EGFP (green) and TH (red). (D–I) Expression levels of c-Fos at the SCN, PVN, and SCG. CNO, Clozapine N-oxide; GIRKs, G-protein sensitive inwardly rectifying potassium channels; p* < 0.05.

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  Figure 5. Effects of ganglionic blockade on cardiac dysfunction in a circadian disruption model. (A–D) Difference between weight, heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP) of two groups. (E) Representative images of echocardiography. (F–I) Differences of EF, FS, LVIDs, and LVIDd. (J,K) Masson staining. (L–N) HRV: LF, HF and LF/HF. (O) VF-Threshold. HRV, Heart rate variability; LF, low frequency; HF, the high frequency, the LF/HF ratio, and ventricular fibrillation, VF; p* < 0.05.

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  Figure 6. Sympathetic nervous system is the key link between circadian disruption and cardiac remodeling. Circadian disruption aggravates cardiac remodeling after MI possibly by activating sympathetic nervous system. Circadian information may be carried to the heart by the “SCN-PVN-SCG-Heart” sympathetic axis mechanism. Cardiac remodeling at the transcriptional level is aggravated by circadian disruption, and the changes mainly include cardiac local clock, cardiac nervous system, cardiac muscle contraction, extracellular matrix, lipid metabolism, and inflammation.