Nitric oxide in cardiovascular and renal disease : role of organic nitrates, inorganic nitrate and red blood cells
Author: Zhuge, Zhengbing
Date: 2022-02-25
Location: Biomedicum, Lecture Hall Eva & Georg Klein (D0320), Karolinska Institutet, Solna
Time: 13.00
Department: Inst för fysiologi och farmakologi / Dept of Physiology and Pharmacology
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Thesis (2.675Mb)
Abstract
RATIONALE: Cardiovascular and renal disorders are major health problems, which are often co-existing. Mechanistically, these conditions can be attributed to endothelial dysfunction, a process coupled with reduced nitric oxide (NO) bioavailability. In the vasculature, NO is predominantly formed by endothelial NO-synthase (eNOS), which uses L-arginine and oxygen as substrates. Organic nitrates like glyceryl trinitrate (GTN) are clinically used as an exogenous source of NO, with potent vasodilator actions. Despite their long history of use, the undesired side-effects induced by organic nitrates, such as hypotension, headache and development of tolerance, limit their clinical use and demand a need to develop new nitrate preparations. In addition to the classical NOS system, the nitrate-nitrite-NO pathway can serve as additional source of NO generation. Inorganic nitrate is abundant in certain foods, e.g. leafy green vegetables and beetroot. Stimulating this NOS-independent system, via the diet, has been linked with favorable cardiovascular, metabolic and renal effects in several disease models. Moreover, the recent discovery of existing NOS in red blood cells (RBCs) has started a debate regarding the role and interaction between RBCs and endothelial NOSs in regulation of vascular function.
AIM: This thesis I) characterizes the therapeutic value of restoring NO bioavailability in cardiovascular and renal disease models by using novel organic mononitrate(s) and inorganic nitrate, and II) investigates the potential role and interaction between NOS in RBCs and the endothelium in regulation or modulation of vascular function.
METHODS & RESULTS: Combination of in vivo disease models, ex vivo vessel reactivity as well as in vitro studies were used. Study I-II: A novel organic nitrate 1,3-bis(hexyloxy)propan- 2-yl nitrate (NDHP) was synthesized and functionally characterized. It was found that NDHPderived NO formation was enzymatically mediated by xanthine oxidoreductase (XOR). Moreover, NDHP treatment in contrast to GTN was not subject to tolerance in isolated small arteries and NDHP attenuated angiotensin II-induced hypertension and endothelial dysfunction in rats. Study III: Inorganic nitrate supplementation, increased NO bioactivity, dampened oxidative stress and inflammation and ameliorated mitochondrial abnormalities, which were associated with protection against development of renal ischemia-reperfusion (IR) injuries in mice. This novel approach may have therapeutic value by reducing the risk of acute and chronic kidney disease as well as cardiovascular co-morbidities. Study IV: Using ex vivo co-incubation of isolated RBCs and aortas from eNOS-deficient and control mice, it was shown that RBCs lacking NOS induced oxidative stress and endothelial dysfunction in healthy vessels. This pathological vascular phenotype could be prevented by inhibition of arginase activity and by scavenging of NADPH oxidase-derived reactive oxygen species.
CONCLUSION: Restoring NO bioactivity, by using novel organic nitrates or inorganic nitrate, is coupled with favorable effects in models of cardiorenal disease. In addition, arginase and oxidative stress is involved in the interaction between NOS in RBCs and the endothelium. Future studies are needed to further characterize underlying mechanisms and to investigate the potential therapeutic value.
AIM: This thesis I) characterizes the therapeutic value of restoring NO bioavailability in cardiovascular and renal disease models by using novel organic mononitrate(s) and inorganic nitrate, and II) investigates the potential role and interaction between NOS in RBCs and the endothelium in regulation or modulation of vascular function.
METHODS & RESULTS: Combination of in vivo disease models, ex vivo vessel reactivity as well as in vitro studies were used. Study I-II: A novel organic nitrate 1,3-bis(hexyloxy)propan- 2-yl nitrate (NDHP) was synthesized and functionally characterized. It was found that NDHPderived NO formation was enzymatically mediated by xanthine oxidoreductase (XOR). Moreover, NDHP treatment in contrast to GTN was not subject to tolerance in isolated small arteries and NDHP attenuated angiotensin II-induced hypertension and endothelial dysfunction in rats. Study III: Inorganic nitrate supplementation, increased NO bioactivity, dampened oxidative stress and inflammation and ameliorated mitochondrial abnormalities, which were associated with protection against development of renal ischemia-reperfusion (IR) injuries in mice. This novel approach may have therapeutic value by reducing the risk of acute and chronic kidney disease as well as cardiovascular co-morbidities. Study IV: Using ex vivo co-incubation of isolated RBCs and aortas from eNOS-deficient and control mice, it was shown that RBCs lacking NOS induced oxidative stress and endothelial dysfunction in healthy vessels. This pathological vascular phenotype could be prevented by inhibition of arginase activity and by scavenging of NADPH oxidase-derived reactive oxygen species.
CONCLUSION: Restoring NO bioactivity, by using novel organic nitrates or inorganic nitrate, is coupled with favorable effects in models of cardiorenal disease. In addition, arginase and oxidative stress is involved in the interaction between NOS in RBCs and the endothelium. Future studies are needed to further characterize underlying mechanisms and to investigate the potential therapeutic value.
List of papers:
I. Synthesis and characterization of a novel organic nitrate NDHP: Role of xanthine oxidoreductase-mediated nitric oxide formation. Zhengbing Zhuge, Luciano L Paulo, Arghavan Jahandideh, Maria C R Brandão, Petrônio F Athayde-Filho, Jon O Lundberg, Valdir A Braga, Mattias Carlström, Marcelo F Montenegro. Redox Biology. 2017 Oct; 13:163-169.
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II. The novel organic mononitrate NDHP attenuates hypertension and endothelial dysfunction in hypertensive rats. Luciano L. Paulo, Josiane Campos Cruz, Zhengbing Zhuge, Alynne Carvalho-Galvão, Maria C.R. Brandão, Thiago F. Diniz, Sarah McCann Haworth, Petrônio F. Athayde-Filho, Virginia S. Lemos, Jon O. Lundberg, Marcelo F. Montenegro, Valdir A. Braga, Mattias Carlström. Redox Biology. 2018; 15:182–191.
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III. Renovascular effects of inorganic nitrate following ischemiareperfusion of the kidney. Gensheng Zhang*, Huirong Han*, Zhengbing Zhuge, Fang Dong, Shan Jiang, Wenwen Wang, Drielle D Guimarães, Tomas A Schiffer, En Yin Lai, Lucas Rannier Ribeiro Antonino Carvalho, Ricardo Barbosa Lucena, Valdir A Braga, Eddie Weitzberg, Jon O Lundberg, Mattias Carlstrom. Redox Biology. 2021 Feb; 39:101836. *Equal contribution.
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IV. Red blood cells from endothelial nitric oxide synthase-deficient mice induce vascular dysfunction involving oxidative stress and endothelial Arginase I. Zhengbing Zhuge*, Sarah McCann Haworth*, Carina Nihlén, Lucas Carvalho, Francesca Leo, Andrei L. Kleschyov, Miriam Cortese-Krott, Eddie Weitzberg, Jon O. Lundberg, Mattias Carlstrom. *Equal contribution. [Manuscript]
I. Synthesis and characterization of a novel organic nitrate NDHP: Role of xanthine oxidoreductase-mediated nitric oxide formation. Zhengbing Zhuge, Luciano L Paulo, Arghavan Jahandideh, Maria C R Brandão, Petrônio F Athayde-Filho, Jon O Lundberg, Valdir A Braga, Mattias Carlström, Marcelo F Montenegro. Redox Biology. 2017 Oct; 13:163-169.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. The novel organic mononitrate NDHP attenuates hypertension and endothelial dysfunction in hypertensive rats. Luciano L. Paulo, Josiane Campos Cruz, Zhengbing Zhuge, Alynne Carvalho-Galvão, Maria C.R. Brandão, Thiago F. Diniz, Sarah McCann Haworth, Petrônio F. Athayde-Filho, Virginia S. Lemos, Jon O. Lundberg, Marcelo F. Montenegro, Valdir A. Braga, Mattias Carlström. Redox Biology. 2018; 15:182–191.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Renovascular effects of inorganic nitrate following ischemiareperfusion of the kidney. Gensheng Zhang*, Huirong Han*, Zhengbing Zhuge, Fang Dong, Shan Jiang, Wenwen Wang, Drielle D Guimarães, Tomas A Schiffer, En Yin Lai, Lucas Rannier Ribeiro Antonino Carvalho, Ricardo Barbosa Lucena, Valdir A Braga, Eddie Weitzberg, Jon O Lundberg, Mattias Carlstrom. Redox Biology. 2021 Feb; 39:101836. *Equal contribution.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Red blood cells from endothelial nitric oxide synthase-deficient mice induce vascular dysfunction involving oxidative stress and endothelial Arginase I. Zhengbing Zhuge*, Sarah McCann Haworth*, Carina Nihlén, Lucas Carvalho, Francesca Leo, Andrei L. Kleschyov, Miriam Cortese-Krott, Eddie Weitzberg, Jon O. Lundberg, Mattias Carlstrom. *Equal contribution. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Carlström, Mattias
Co-supervisor: Weitzberg, Eddie; Montenegro, Marcelo; Lai, Enyin; Persson, Erik
Issue date: 2022-02-03
Rights:
Publication year: 2022
ISBN: 978-91-8016-488-7
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