Inhibition of endoplasmic reticulum stress improves coronary artery function in the spontaneously hypertensive rats

Abstract

Endoplasmic reticulum (ER) stress has been shown to play a critical role in the pathogenesis of cardiovascular complications. However, the role and mechanisms of ER stress in hypertension remain unclear. Thus, we hypothesized that enhanced ER stress contributes to the maintenance of hypertension in spontaneously hypertensive rats (SHRs). Sixteen-week old male SHRs and Wistar Kyoto Rats (WKYs) were used in this study. The SHRs were treated with ER stress inhibitor (Tauroursodeoxycholic acid; TUDCA, 100 mg/kg/day) for two weeks. There was a decrease in systolic blood pressure in SHR treated with TUDCA. The pressure-induced myogenic tone was significantly increased, whereas endothelium-dependent relaxation was significantly attenuated in SHR compared with WHY. Interestingly, treatment of ER stress inhibitor normalized myogenic responses and endothelium-dependent relaxation in SHR. These data were associated with an increase in expression or phosphorylation of ER stress markers (Bip, ATF6, CHOP, IRE1, XBP1, PERK, and eIF2α) in SHRs, which were reduced by TUDCA treatment. Furthermore, phosphorylation of MLC20 was increased in SHRs, which was reduced by the treatment of TUDCA. Therefore, our results suggest that ER stress could be a potential target for hypertension.

Rapamycin Rescues Endoplasmic Reticulum Stress–Induced Dry Eye Syndrome in Mice

“…Sustained activation of XBP-1 causes apoptosis and inflammation, although XBP-1 is required for biosynthesis in exocrine glands. 38,39 It has been reported that XBP-1 and GRP78 in the conjunctiva is induced by IFN-c in Sjögren syndrome, 6 which is compatible with this study. In this study, CHOP also increased in the lacrimal glands of TM group.…”

Activation of AMP‐activated protein kinase by metformin ablates angiotensin II‐induced endoplasmic reticulum stress and hypertension in mice in vivo

“…Emerging evidence from humans (Du et al , ) as well as animal models indicates that enhanced ER stress is an important contributor to the development of hypertension (Hasty and Harrison, ; Liang et al , ). For example, prolonged ER stress in the rostral ventrolateral medulla contributes to oxidative stress‐associated neurogenic hypertension in spontaneously hypertensive rats (Chao et al , ), and accordingly, the ER stress inhibitor TUDCA decreases sBP in the spontaneously hypertensive rats (Choi et al , ). 4‐Phenylbutyric acid (4‐PBA), which is an ER stress inhibitor that is structurally unrelated to TUDCA, also lowers monocrotaline‐induced pulmonary artery pressure in male Wistar rats (Wu et al , ).…”

Endoplasmic reticulum stress in the pathogenesis of hypertension

“…; Choi et al . ). Chronic treatment with ER chemical chaperones reduces arterial blood pressure and restores altered vascular function in spontaneous models of hypertension (Spitler et al .…”

“…; Choi et al . ). Together, notwithstanding the caveats of systemic administration of ER stress modulators or the influence of perfusion pressure on vascular function (as discussed above), these findings indicate that vascular ER stress occurs in various forms of hypertension and is associated with chronic elevations in blood pressure.…”