Endoplasmic Reticulum Stress Participates in Aortic Valve Calcification in Hypercholesterolemic Animals
Objectives—Aortic valve (AV) calcification occurs via a pathophysiological process that includes lipoprotein deposition, inflammation, and osteoblastic differentiation of valvular interstitial cells. Here, we investigated the association between endoplasmic reticulum (ER) stress and AV calcification.
Approach and Results—We identified ER stress activation in AV of patients with calcified AV stenosis. We generated an AV calcification model in hypercholesterolemic rabbits and mice, respectively, and found marked AV ER stress induction. Classical ER stress inhibitor, tauroursodeoxycholic acid, administration markedly prevented AV calcification, and attenuated AV osteoblastic differentiation and inflammation in both rabbit and mouse models of AV calcification via inhibition of ER stress. In cultured valvular interstitial cells, we found that oxidized low-density lipoprotein caused ER stress in a cytosolic [Ca]2+i-dependent manner. Oxidized low-density lipoprotein promoted osteoblastic differentiation via ER-stress–mediated protein kinase-like ER kinase/activation of transcription factor 4/osteocalcin and inositol-requiring transmembrane kinase and endonuclease-1α/spliced X-box–binding protein 1/Runx2 pathway, and induced inflammatory responses through inositol-requiring transmembrane kinase and endonuclease-1α/c-Jun N-terminal kinase and inositol-requiring transmembrane kinase and endonuclease-1α/nuclear factor-κB signaling in valvular interstitial cells. Inhibition of ER stress by either tauroursodeoxycholic acid or 4-phenyl butyric acid could both suppress oxidized low-density lipoprotein–induced osteoblastic differentiation and inflammatory responses in valvular interstitial cells.
Conclusions—These data provide novel evidence that ER stress participates in AV calcification development, and suggest that ER stress may be a novel target for AV calcification prevention and treatment.
- Received July 29, 2012.
- Accepted July 24, 2013.
- © 2013 American Heart Association, Inc.