Inactivation of Cys⁶⁷⁴ in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase

Abstract

Background and Purpose The kidney is essential in regulating sodium homeostasis and BP. The irreversible oxidation of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is increased in the renal cortex of hypertensive mice. Whether inactivation of C674 promotes hypertension is unclear. Here we have investigated the effects on BP of the inactivation of C674, and its role in the kidney. Experimental Approach We used heterozygous SERCA2 C674S knock‐in (SKI) mice, where half of C674 was substituted by serine, to represent partial irreversible oxidation of C674. The BP, urine volume, and urine composition of SKI mice and their littermate wild‐type (WT) mice were measured. The kidneys were collected for cell culture, Na+/K+‐ATPase activity, protein expression, and immunohistological analysis. Key Results Compared with WT mice, SKI mice had higher BP, lower urine volume and sodium excretion, up‐regulated endoplasmic reticulum (ER) stress markers and soluble epoxide hydrolase (sEH), and down‐regulated dopamine D1 receptors in renal cortex and cells from renal proximal tubule. ER stress and sEH were mutually regulated, and both upstream of D1 receptors. Inhibition of ER stress or sEH up‐regulated expression of D1 receptors, decreased the activity of Na+/K+‐ATPase, increased sodium excretion, and lowered BP in SKI mice. Conclusions and Implications The inactivation of SERCA2 C674 promotes the development of hypertension by inducing ER stress and sEH. Our study highlights the importance of C674 redox status in BP control and the contribution of SERCA2 to sodium homeostasis and BP in the kidney.

Profile and Functional Prediction of Plasma Exosome-Derived CircRNAs From Acute Ischemic Stroke Patients

“…According to GO annotations of host genes, the ribosome and ribonucleoprotein could be impacted in AIS, disordering RNA translation/regulation and protein processing in the endoplasmic reticulum, which was highlighted by KEGG analysis. It has been reported that endoplasmic reticulum stress induced by abnormal protein processing takes place in atherosclerosis ( Tabas, 2010 ; Huang et al, 2018 ) and hypertension ( Naiel et al, 2019 ; Liu et al, 2020 ), for which the underlying mechanism could be the dysfunction of vascular endothelial cells by endoplasmic reticulum stress, like excessive apoptosis ( Sun et al, 2015 ; Carlisle et al, 2016 ). Moreover, by KEGG pathway analysis, focal adhesion and leukocyte transendothelial migration were significantly enriched.…”

Cross-Talk between Mechanosensitive Ion Channels and Calcium Regulatory Proteins in Cardiovascular Health and Disease

“…Activation of SERCA can accelerate the reuptake of Ca 2+ by SR, which would improve the diastolic dysfunction of myocardium, and result in strong antiarrhythmic effect [81,82]. Our groups found that the S-glutathiolation of the amino acid residue Cys674 (C674) is key to the increase of the activity in SERCA2 under physiological conditions [83,84], but this post-translational protein modification is prevented by the irreversible oxidation of C674 thiol in pathology hallmarked by high level of ROS, including atherosclerosis, aortic aneurysms, aging and hypertension [83,[85][86][87]. The substitution of the SERCA2 C674 by serine causes impaired angiogenesis following hindlimb ischemia by interrupting the physiological functions of endothelial cells and macrophage [88,89], increases blood pressure by inducing sodium retention and ER stress in the kidney [87], exacerbates angiotensin II-induced aortic aneurysm by switching the phenotypes in aortic SMCs [90], aggravates high fat diet-induced aortic atherosclerosis by evoking inflammatory response in endothelial cells and macrophage (our unpublished data), promotes pulmonary vascular remodeling, and protects against left ventricular dilation caused by chronic ascending aortic constriction [91].…”

Inactivation of SERCA2 Cys674 accelerates aortic aneurysms by suppressing PPARγ

“…This may be attributed to the clearly shown degradation of elastin in several adjacent parts of SKI aorta, resulting in the formation of large aneurysms in the longitudinal direction of the aorta. In addition, in SKI mice, blood pressure increased by 10-20 mmHg (Liu et al, 2020), which may cause aortic dissection to some extent, resulting in aneurysm formation along the aorta, rather than transverse lesions. In the model of aortic dissection induced by β-aminopropionitrile, the prognosis of SKI mice is more serious than of WT mice, which further supports the importance of redox C674 in maintaining aortic homeostasis.…”

“…Sarco/endoplasmic reticulum calcium ATPase (SERCA) is a key enzyme to maintain calcium homeostasis by taking up Ca 2+ from cytosol to sarcoplasmic reticulum and endoplasmic reticulum. SERCA2 is the main subtype of SERCA in the vasculature, and the S ‐glutathiolation of the amino acid residue Cys 674 (C674) is key to increase the activity of SERCA2 under physiological conditions (Adachi et al, 2004; Tong et al, 2008), but this post‐translational protein modification is prevented by the irreversible oxidation of C674 thiol in pathological situations characterized by high levels of ROS, such as ageing, diabetes mellitus, atherosclerosis and hypertension (Adachi et al, 2004; Liu et al, 2020; Qin et al, 2013; Ying et al, 2008), which are risk factors for aortic aneurysms. Such irreversible oxidation of C674 in SERCA2 occurred widely in mouse and human aortic aneurysms (Que et al, 2020).…”