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The sympathetic transmitter norepinephrine inhibits VSMC proliferation induced by TGF? by suppressing the expression of the TGF? receptor ALK5 in aorta remodeling.

ABSTRACT: The sympathetic system is involved in the arterial diseases, but its mechanism remains poorly understood. The present study aimed to explore the impact of the sympathetic neurotransmitter norepinephrine (NE) on transforming growth factor (TGF) ? signaling and the role of NE in aortic remodeling. Guanethidine was used to induce a regional chemical sympathetic denervation (CSD) in angiotensin II (AngII) and ??aminopropionitrile (BAPN)?induced aortic aneurysm models. The diameter of the aorta was measured, and elastic fiber staining was performed. TGF? type I receptor kinase (ALK5) expression in rat aortic NE?treated vascular smooth muscle cells (VSMCs) was detected by reverse transcription?quantitative PCR and western blotting. The effects of NE and ALK5 overexpression on migration, proliferation, apoptosis and TGF? signaling were also evaluated. Furthermore, adrenergic receptor blockers were used to determine which receptor was involved in the modulation on TGF? signaling by NE. The results of the present study demonstrated that CSD protected rats from AngII+BAPN?induced aortic remodeling and aneurysm formation. Compared with the control group, NE inhibited VSMC proliferation and migration, but promoted apoptosis by suppressing ALK5 expression, reversing the effects of TGF? signaling through the suppression of the SMAD?dependent canonical pathway and promotion of the non?canonical pathway. These effects were prevented by ALK5 overexpression. The inhibition of ?? or ??adrenergic receptors alleviated the NE?mediated suppression of ALK5 expression. In conclusion, regional CSD protected rats from aortic aneurysm. NE inhibited SMAD2/3?dependent TGF? signaling by suppressing ALK5 expression, which may serve an important role in VSMC biological functions. Both ?? and ??adrenergic receptors were involved in the regulation of ALK5 expression by NE. Abnormal sympathetic innervation of the aorta may be used as a therapeutic target in aortic diseases.

SUBMITTER: Hu Z

PROVIDER: S-EPMC7248509 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The sympathetic transmitter norepinephrine inhibits VSMC proliferation induced by TGFβ by suppressing the expression of the TGFβ receptor ALK5 in aorta remodeling.

Hu Zhipeng Z Li Bowen B Wang Zhiwei Z Hu Xiaoping X Zhang Min M Chen Ruoshi R Wu Qi Q Jia Fangyuan F

Molecular medicine reports 20200422 1

The sympathetic system is involved in the arterial diseases, but its mechanism remains poorly understood. The present study aimed to explore the impact of the sympathetic neurotransmitter norepinephrine (NE) on transforming growth factor (TGF) β signaling and the role of NE in aortic remodeling. Guanethidine was used to induce a regional chemical sympathetic denervation (CSD) in angiotensin II (AngII) and β‑aminopropionitrile (BAPN)‑induced aortic aneurysm models. The diameter of the aorta was m ...[more]

PMID: 32319652

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Project description:Injury-induced stenosis is a serious vascular complication. We previously reported that p38? (MAPK14), a redox-regulated p38MAPK family member was a negative regulator of the VSMC contractile phenotype in vitro. Here we evaluated the function of VSMC-MAPK14 in vivo in injury-induced neointima hyperplasia and the underlying mechanism using an inducible SMC-MAPK14 knockout mouse line (iSMC-MAPK14-/-). We show that MAPK14 expression and activity were induced in VSMCs after carotid artery ligation injury in mice and ex vivo cultured human saphenous veins. While the vasculature from iSMC-MAPK14-/- mice was indistinguishable from wildtype littermate controls at baseline, these mice exhibited reduced neointima formation following carotid artery ligation injury. Concomitantly, there was an increased VSMC contractile protein expression in the injured vessels and a decrease in proliferating cells. Blockade of MAPK14 through a selective inhibitor suppressed, while activation of MAPK14 by forced expression of an upstream MAPK14 kinase promoted VSMC proliferation in cultured VSMCs. Genome wide RNA array combined with VSMC lineage tracing studies uncovered that vascular injury evoked robust inflammatory responses including the activation of proinflammatory gene expression and accumulation of CD45 positive inflammatory cells, which were attenuated in iSMC-MAPK14-/- mice. Using multiple pharmacological and molecular approaches to manipulate MAPK14 pathway, we further confirmed the critical role of MAPK14 in activating proinflammatory gene expression in cultured VSMCs, which occurs in a p65/NFkB-dependent pathway. Finally, we found that NOX4 contributes to MAPK14 suppression of the VSMC contractile phenotype. Our results revealed that VSMC-MAPK14 is required for injury-induced neointima formation, likely through suppressing VSMC differentiation and promoting VSMC proliferation and inflammation. Our study will provide mechanistic insights into therapeutic strategies for mitigation of vascular stenosis.

Project description:BackgroundHeart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model.MethodsHFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined.ResultsBlood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment.Conclusion9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.

Dataset Information

The sympathetic transmitter norepinephrine inhibits VSMC proliferation induced by TGF? by suppressing the expression of the TGF? receptor ALK5 in aorta remodeling.

Publications

The sympathetic transmitter norepinephrine inhibits VSMC proliferation induced by TGFβ by suppressing the expression of the TGFβ receptor ALK5 in aorta remodeling.

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