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https://doi.org/10.1161/HYPERTENSIONAHA.122.19103
Title: | S-Nitrosylation-Mediated Reduction of Ca(V)1.2 Surface Expression and Open Probability Underlies Attenuated Vasoconstriction Induced by Nitric Oxide | Authors: | Hu, Zhenyu Zhang, Bo Lim, Leon Jian Ying Loh, Wei Zhern Kelvin Yu, Dejie Tan, Bryce Wei Quan Liang, Mui Cheng Huang, Zhongwei Leo, Chen Huei Huang, Hua Soong, Tuck Wah |
Keywords: | Science & Technology Life Sciences & Biomedicine Peripheral Vascular Disease Cardiovascular System & Cardiology Ca(V)1 2 channel hypertension lysosome open probability S-nitrosylation SOLUBLE GUANYLATE-CYCLASE CALCIUM-CHANNELS ANGIOTENSIN-II PROTEIN-KINASE IN-VITRO INHIBITION CONTRACTION RELAXATION MECHANISM |
Issue Date: | 1-Dec-2022 | Publisher: | LIPPINCOTT WILLIAMS & WILKINS | Citation: | Hu, Zhenyu, Zhang, Bo, Lim, Leon Jian Ying, Loh, Wei Zhern Kelvin, Yu, Dejie, Tan, Bryce Wei Quan, Liang, Mui Cheng, Huang, Zhongwei, Leo, Chen Huei, Huang, Hua, Soong, Tuck Wah (2022-12-01). S-Nitrosylation-Mediated Reduction of Ca(V)1.2 Surface Expression and Open Probability Underlies Attenuated Vasoconstriction Induced by Nitric Oxide. HYPERTENSION 79 (12) : 2854-2866. ScholarBank@NUS Repository. https://doi.org/10.1161/HYPERTENSIONAHA.122.19103 | Abstract: | Background: L-type CaV1.2 calcium channel, the primary gateway for Ca2+ influx in smooth muscles, is widely regulated by multiple posttranslational modifications, such as protein kinase-mediated phosphorylation and nitric oxide-induced S-nitrosylation. However, the effect of S-nitrosylation on CaV1.2 channel function and its role in arterial contractility are not well understood. Methods: Electrophysiological recordings, Ca2+ and confocal imaging, and biochemical assays were used to functionally characterize S-nitrosylated CaV1.2 channels in vitro, while pressure myography and tail-cuff blood pressure measurement were conducted to evaluate the physiological effects of CaV1.2 S-nitrosylation ex vivo and in vivo. Results: S-nitrosylation significantly reduced the CaV1.2 current density by promoting lysosomal degradation that leads to decreased levels of total and surface CaV1.2 channel proteins in a CaVβ-independent manner and reducing the open probability of CaV1.2 channel. Mechanistically, the Cys1180 and Cys1280 residues within CaV1.2 channel have been determined as the molecular targets for S-nitrosylation as substitution of either Cys1180 or Cys1280 for serine resulted in substantial reduction of S-nitrosylation levels. Of note, CaV1.2 S-nitrosylation levels were significantly reduced in arteries isolated from both spontaneously hypertensive rats and patients with pulmonary hypertension. Moreover, mouse resistance arteries incubated with S-nitrosocysteine displayed much lower contractility and spontaneously hypertensive rats injected with S-nitrosocysteine also showed significantly reduced blood pressure, suggesting that reduced S-nitrosylation contributes to the upregulation of CaV1.2 channel activity in hypertensive arteries. Conclusions: This study provides strong evidence that S-nitrosylation-mediated downregulation of CaV1.2 channels is via 2 distinctive mechanisms and the findings offer potential pathways for therapeutic inventions in hypertension. | Source Title: | HYPERTENSION | URI: | https://scholarbank.nus.edu.sg/handle/10635/237717 | ISSN: | 0194-911X 1524-4563 |
DOI: | 10.1161/HYPERTENSIONAHA.122.19103 |
Appears in Collections: | Staff Publications Elements |
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S-nitrosylation-mediated reduction of Cav1.2 surface expression_Hypertension_Dec 2022.pdf | Published version | 2.96 MB | Adobe PDF | CLOSED | None |
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