Aberrant Endoplasmic Reticulum Stress in Vascular Smooth Muscle Increases Vascular Contractility and Blood Pressure in Mice Deficient of AMP-Activated Protein Kinase-α2 In Vivo

Abstract

Objective The endoplasmic reticulum (ER) plays a critical role in ensuring proper folding of newly synthesized proteins. Aberrant ER stress is reported to play a causal role in cardiovascular diseases. However, the effects of ER stress on vascular smooth muscle contractility and blood pressure remain unknown. The aim of this study was to investigate whether aberrant ER stress causes abnormal vasoconstriction and consequent high blood pressure in mice. Methods and Results ER stress markers, vascular smooth muscle contractility, and blood pressure were monitored in mice. Incubation of isolated aortic rings with tunicamycin or MG132, 2 structurally unrelated ER stress inducers, significantly increased both phenylephrine-induced vasoconstriction and the phosphorylation of myosin light chain (Thr18/Ser19), both of which were abrogated by pretreatment with chemical chaperones or 5-Aminoimidazole-4-carboxamide ribonucleotide and metformin, 2 potent activators for the AMP-activated protein kinase. Consistently, administration of tauroursodeoxycholic acid or 4-phenyl butyric acid, 2 structurally unrelated chemical chaperones, in AMP-activated protein kinase-α2 knockout mice lowered blood pressure and abolished abnormal vasoconstrictor response of AMP-activated protein kinase-α2 knockout mice to phenylephrine. Consistently, tunicamycin (0.01 μ/g per day) infusion markedly increased both systolic and diastolic blood pressure, both of which were ablated by coadministration of 4-phenyl butyric acid. Furthermore, 4-phenyl butyric acid or tauroursodeoxycholic acid, which suppressed angiotensin II infusion–induced ER stress markers in vivo, markedly lowered blood pressure in angiotensin II–infused mice in vivo. Conclusion We conclude that ER stress increases vascular smooth muscle contractility resulting in high blood pressure, and AMP-activated protein kinase activation mitigates high blood pressure through the suppression of ER stress in vivo.

Involvement of Endoplasmic Reticulum Stress–Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3–Induced Acute Viral Myocarditis

“…19 It has been proved to be protective in various diseases, such as diabetes mellitus, hypertension, calcification, and even cardiac dysfunction via prevention of ER stress. 11,19,41,42 We also observed that TUDCA administration markedly suppressed cardiac ER stress and CHOP induction, prevented cardiomyocytes apoptosis, cardiac inflammation and injury, cardiac dysfunction, and increased survival rate in our CVB3 inoculation-induced AVMC model. This further indicates ER stress in AVMC is not merely a secondary consequence.…”

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

“…Chemical induction of ER stress using either tunicamycin or MG-132 has recently been linked with increased contractility in SMCs (38). Increased cytoplasmic calcium levels due to ER stress lead to calcium-calmodulin complexes, which bind and activate myosin light chain kinase, leading to increased myosin regulatory light chain phosphorylation and SMC contraction (40).…”

“…Therefore, this model is not as physiologically relevant as the SM1 model in which Myh11 expression is increased only 5-fold. Increased contractility due to ER stress induced by in vivo tunicamycin infusion also leads to increased systolic blood pressures (38). Although the SM1 mouse strain was lost prior to documentation of blood pressures, it is interesting to note that many of the patients with 16p13.1 duplications are hypertensive (3).…”

“…As described above, the percentage of polymerized actin is equivalent in SM1 and NTG cells, so an alternative mechanism must drive increased cellular contraction. Previous studies have shown that increased contractility can be driven by increased calcium release from the ER as a result of ER stress (38,39). Therefore, we sought to determine whether baseline cytosolic calcium concentrations were increased in SM1 cells and, if so, would the cells respond aberrantly to thapsigargin, a drug that inhibits calcium reuptake into the ER.…”

“…Increased Contraction and Calcium Signaling in SM1 Cells-A recent study linked increased ER stress response with increased contractility in the aorta (38). Intriguingly, SM1 transgenic mice exhibit increased aortic contractility in vivo (13).…”