Hypertension-induced cardiac impairment is reversed by the inhibition of endoplasmic reticulum stress

BAL N. B., HAN S., KİREMİTCİ S., SADİ G., Uludag O., DEMİREL YILMAZ E.

JOURNAL OF PHARMACY AND PHARMACOLOGY, cilt.71, sa.12, ss.1809-1821, 2019 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 71 Sayı: 12
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1111/jphp.13169
  • Dergi Adı: JOURNAL OF PHARMACY AND PHARMACOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1809-1821
  • Anahtar Kelimeler: endoplasmic reticulum stress, heart, hypertension, tauroursodeoxycholic acid, NF-KAPPA-B, ANGIOTENSIN-II, ER STRESS, APOPTOSIS, HEART, HYPERTROPHY, DYSFUNCTION, RESPONSES, OVERLOAD, DAMAGE
  • Gazi Üniversitesi Adresli: Evet

Özet

Objectives Endoplasmic reticulum stress (ERS) has been shown to play a crucial role in the pathogenesis of hypertension. However, the role and mechanisms of ERS on hypertension-induced cardiac functional and morphological changes remain unclear. In this study, the effect of ERS inhibition with tauroursodeoxycholic acid (TUDCA) on hypertension-induced cardiac remodelling was examined. Methods Hypertension was induced by deoxycorticosterone-acetate (DOCA) and salt administration in uni-nephrectomized rats for 12 weeks. TUDCA was administered for the last four weeks. Rhythmic activity and contractions of the right atrium and left papillary muscle (LPM) were recorded. In the left ventricle, the expression of various proteins was examined and histopathological evaluation was performed. Key findings Hypertension-induced increments in systolic blood pressure and ventricular contractions were reversed by TUDCA. In the hypertensive heart, while expressions of glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated protein kinase-like ER kinase (p-PERK), sarcoplasmic reticulum Ca-ATPase-2 (SERCA2), matrix metalloproteinase-2 (MMP-2) and nuclear NF-kappa B p65 increased; Bcl-2 (B-cell lymphoma-2) expression decreased and the altered levels of all these markers were restored by TUDCA. In the microscopic examination, TUDCA treatment attenuated hypertension-stimulated cardiac inflammation and fibrosis. Conclusions These results suggest that ERS inhibition may ameliorate cardiac contractility through improving ERS-associated calcium mishandling, apoptosis, inflammation and fibrosis, thereby offering therapeutic potential in hypertension-induced cardiac dysfunction.