2. Academic Validation
  3. Blocking mitochondrial cyclophilin D ameliorates TSH-impaired defensive barrier of artery

Blocking mitochondrial cyclophilin D ameliorates TSH-impaired defensive barrier of artery

  • Redox Biol. 2018 May;15:418-434. doi: 10.1016/j.redox.2018.01.004.
Xiaojing Liu 1,  Heng Du 2,  Qiang Chai 3,  Qing Jia 3,  Lu Liu 1,  Meng Zhao 1,  Jun Li 4,  Hui Tang 4,  Wenbin Chen 5,  Lifang Zhao 1,  Li Fang 1,  Ling Gao 6,  Jiajun Zhao 7
Affiliations

Affiliations

  • 1 Deparment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
  • 2 Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, United States.
  • 3 Department of Cardiovascular Disease, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250001, China.
  • 4 Department of Pharmacy, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
  • 5 Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
  • 6 Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China; Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China. Electronic address: [email protected].
  • 7 Deparment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China. Electronic address: [email protected].
PMID: 29353219 DOI: 10.1016/j.redox.2018.01.004
Abstract

Aims: Endothelial cells (ECs) constitute the defensive barrier of vasculature, which maintains the vascular homeostasis. Mitochondrial oxidative stress (mitoOS) in ECs significantly affects the initiation and progression of vascular diseases. The higher serum thyroid stimulating hormone (TSH) level is being recognized as a nonconventional risk factor responsible for the increased risk of cardiovascular diseases in subclinical hypothyroidism (SCH). However, effects and underlying mechanisms of elevated TSH on ECs are still ambiguous. We sought to investigate whether cyclophilin D (CypD), emerging as a crucial mediator in mitoOS, regulates effects of TSH on ECs.

Methods and results: SCH patients with TSH > = 10mIU/L showed a positive correlation between serum TSH and endothelin-1 levels. When TSH levels declined to normal in these subjects after levothyroxine therapy, serum endothelin-1 levels were significantly reduced. Supplemented with exogenous thyroxine to keep normal thyroid Hormones, thyroid-specific TSH Receptor (TSHR)-knockout mice with injection of exogenous TSH exhibited elevated serum TSH levels, significant endothelial oxidative injuries and disturbed endothelium-dependent vasodilation. However, Tshr-/- mice resisted to TSH-impaired vasotonia. We further confirmed that elevated TSH triggered excessive mitochondrial permeability transition pore (mPTP) opening and mitochondrial oxidative damages in mouse aorta, as well as in cultured ECs. Genetic or pharmacological inhibition of CypD (the key regulator for mPTP opening) attenuated TSH-induced mitochondrial oxidative damages and further rescued endothelial functions. Finally, we confirmed that elevated TSH could activate CypD by enhancing CypD acetylation via inhibiting adenosine monophosphate-activated protein kinase/sirtuin-3 signaling pathway in ECs.

Conclusions: These findings reveal that elevated TSH triggers mitochondrial perturbations in ECs and provide insights that blocking mitochondrial CypD enhances the defensive ability of ECs under TSH exposure.

Keywords

Cyclophilin D; Endothelial cell; Mitochondria; Oxidative stress; Thyroid stimulating hormone.

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