Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis

  • Wang P
  • Xu T
  • Guan Y
 et al. 
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AIMS: 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. METHODS AND 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 mug/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 mug/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRalpha1, rather than TRbeta1 and TRbeta2 receptors. TRalpha1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone. CONCLUSION: These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRalpha1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease.

Author-supplied keywords

  • Apoptosis
  • Atherosclerosis
  • Hypothyroidism
  • Metabolic cardiovascular disease
  • Thyroid hormone receptor
  • Vascular smooth muscle cell

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  • Pei Wang

  • Tian Ying Xu

  • Yun Feng Guan

  • Yan Zhao

  • Zhi Yong Li

  • Xiao Hong Lan

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