title: Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis.
abstract: OBJECTIVE
  Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear.
  
  
  RESULTS
  Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone.
  
  
  CONCLUSIONS
  These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRα1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease.
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Tian-Ying
authors.initials: TY
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Lan
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China Department of Pharmacology and Pharmacy and State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China cymiao@smmu.edu.cn.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Miao
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology*; D002478:Cells, Cultured; D007037:Hypothyroidism / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology*; D011441:Propylthiouracil / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D037021:Thyroid Hormone Receptors alpha / Q000502:physiology; D037042:Thyroid Hormone Receptors beta / Q000502:physiology; D013963:Thyroid Hormones / Q000172:deficiency
chemical_list: D001057:Apolipoproteins E; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D011441:Propylthiouracil
keywords: Apoptosis; Atherosclerosis; Hypothyroidism; Metabolic cardiovascular disease; Thyroid hormone receptor; Vascular smooth muscle cell