Mitochondrial Isolevuglandins Contribute to Vascular Oxidative Stress and Mitochondria-Targeted Scavenger of Isolevuglandins Reduces Mitochondrial Dysfunction and Hypertension

Dikalova, Anna; Mayorov, Vladimir; Xiao, Liang; Panov, Alexander; Amarnath, Venkataraman; Zagol-Ikapitte, Irène; Vergeade, Aurélia; Ao, Mingfang; Yermalitsky, Valery; Nazarewicz, Ryszard; Boutaud, Olivier; Lopez, Marcos G.; Billings, Frederic T.; Davies, Sean S.; Roberts, L. Jackson; Harrison, David G.; Dikalov, Sergey

doi:10.1161/hypertensionaha.120.15236

Cited by 23 publications

(20 citation statements)

References 74 publications

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“…This is notable, as urinary F2-isoprostane is reduced by treatment with the non-specific antioxidant alpha tocopherol (39,40). These data support the idea that the beneficial effects of PPM are not due to general inhibition of lipid peroxidation or metal ion chelation but to reactive lipid (11,31,38,41,42).…”

Section: Results In Tecs and Lecs Indicate That The Highly Reactive L...supporting

confidence: 62%

Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

Zhong¹,

Yang²,

Shelton³

et al. 2022

JCI Insight

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Lipoprotein modification by reactive dicarbonyls, including isolevuglandin (IsoLG), produces dysfunctional particles. Kidneys participate in lipoprotein metabolism, including tubular uptake. However, the process beyond the proximal tubule is unclear, as is the effect of kidney injury on this pathway. We found that patients and animals with proteinuric injury have increased urinary apolipoprotein AI (apoAI), IsoLG, and IsoLG adduct enrichment of the urinary apoAI fraction compared with other proteins. Proteinuric mice, induced by podocyte specific injury, showed more tubular absorption of IsoLG-apoAI and increased expression of lipoprotein transporters in proximal tubular cells compared with uninjured animals. Renal lymph reflects composition of the interstitial compartment, and showed increased apoAI and IsoLG in proteinuric animals, supporting a tubular cell-interstitium-lymph pathway for renal handling of lipoproteins. IsoLG-modified apoAI was not only a marker of renal injury, but also directly damaged renal cells. IsoLG-apoAI increased inflammatory cytokines in cultured tubular epithelial cells, activated lymphatic endothelial cells and caused greater contractility of renal lymphatic vessels than unmodified apoAI. In vivo, inhibition of IsoLG by a dicarbonyl scavenger reduced both albuminuria and urinary apoAI and decreased tubular epithelial cell and lymphatic endothelial cell injury, lymphangiogenesis, and interstitial fibrosis.Our results indicate that IsoLG-modified apolipoprotein AI is a novel pathogenic mediator and therapeutic target in kidney disease.

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Section: Results In Tecs and Lecs Indicate That The Highly Reactive L...supporting

confidence: 62%

Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

Zhong¹,

Yang²,

Shelton³

et al. 2022

JCI Insight

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“…In RVLM, transcriptional upregulation of sod2 protects against mitochondrial oxidative stress and hypertension in Ang II treatment in normotensive rats [ 61 ]. SOD2 also participates in the protection again hypertension and cardiovascular complications conferred by the mitochondria-target antioxidants [ 62 ]. Nrf2 is the master regulator of antioxidant genes and, hence, of antioxidant status.…”

Section: Discussionmentioning

confidence: 99%

Disparate Roles of Oxidative Stress in Rostral Ventrolateral Medulla in Age-Dependent Susceptibility to Hypertension Induced by Systemic l-NAME Treatment in Rats

Rauchová

Chan

2022

Biomedicines

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This study aims to investigate whether tissue oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, plays an active role in age-dependent susceptibility to hypertension in response to nitric oxide (NO) deficiency induced by systemic L-NAME treatment, and to decipher the underlying molecular mechanisms. Systolic blood pressure (SBP) and heart rate (HR) in conscious rats were recorded, along with measurements of plasma and RVLM level of NO and reactive oxygen species (ROS), and expression of mRNA and protein involved in ROS production and clearance, in both young and adult rats subjected to intraperitoneal (i.p.) infusion of L-NAME. Pharmacological treatments were administered by oral gavage or intracisternal infusion. Gene silencing of target mRNA was made by bilateral microinjection into RVLM of lentivirus that encodes a short hairpin RNA (shRNA) to knock down gene expression of NADPH oxidase activator 1 (Noxa1). We found that i.p. infusion of L-NAME resulted in increases in SBP, sympathetic neurogenic vasomotor activity, and plasma norepinephrine levels in an age-dependent manner. Systemic L-NAME also evoked oxidative stress in RVLM of adult, but not young rats, accompanied by augmented enzyme activity of NADPH oxidase and reduced mitochondrial electron transport enzyme activities. Treatment with L-arginine via oral gavage or infusion into the cistern magna (i.c.), but not i.c. tempol or mitoQ10, significantly offset the L-NAME-induced hypertension in young rats. On the other hand, all treatments appreciably reduced L-NAME-induced hypertension in adult rats. The mRNA microarray analysis revealed that four genes involved in ROS production and clearance were differentially expressed in RVLM in an age-related manner. Of them, Noxa1, and GPx2 were upregulated and Duox2 and Ucp3 were downregulated. Systemic L-NAME treatment caused greater upregulation of Noxa1, but not Ucp3, mRNA expression in RVLM of adult rats. Gene silencing of Noxa1 in RVLM effectively alleviated oxidative stress and protected adult rats against L-NAME-induced hypertension. These data together suggest that hypertension induced by systemic L-NAME treatment in young rats is mediated primarily by NO deficiency that occurs both in vascular smooth muscle cells and RVLM. On the other hand, enhanced augmentation of oxidative stress in RVLM may contribute to the heightened susceptibility of adult rats to hypertension induced by systemic L-NAME treatment.

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“…To test the pathological role of mitochondrial isolevuglandins we developed mitochondria-targeted scavenger of isoLGs, mito2HOBA. It was found that mito2HOBA reduces protein-isolevuglandins adducts, improves deacetylation of mitochondrial proteins, improves mitochondrial and endothelial functions, and reduces hypertension [ 23 ▪▪ ]. We propose that metabolic conditions downregulate Sirt3 activity due to decrease in NAD+ and increase in Acetyl-CoA while oxidative stress causes redox inactivation of Sirt3.…”

Section: Impairment Of Sirt3 In Pathological Conditionsmentioning

confidence: 99%

“…In recent studies, we proposed that oxidative stress can directly contribute to Sirt3 inactivation due to formation of harmful lipid peroxidation products, isolevuglandins, in mitochondria. We discovered 250% increase in mitochondrial isolevuglandins in arterioles isolated from patients with essential hypertension [ 23 ▪▪ ]. Interestingly, scavenger of mitochondrial isolevuglandins, mito2HOBA, protects Sirt3 activity, improves SOD2 deacetylation and inhibits endothelial oxidative stress.…”

Section: Impairment Of Sirt3 In Pathological Conditionsmentioning

confidence: 99%

Mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension

Dikalov

Dikalova

2021

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review Hypertension is a multifactorial disorder involving perturbations of the vasculature, the kidney, and the central nervous system. Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure. Despite treatment with multiple drugs, 37% of hypertensive patients remain hypertensive, likely due to the mechanisms contributing to blood pressure elevation that are not affected by current treatments. This review focuses on recently described novel role of mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension. Recent findings In the past several years, we have shown that the mitochondria are dysfunctional in hypertension; however, the role of mitochondria in the pathogenesis of hypertension remains elusive. We recently showed that patients with essential hypertension have decreased levels of the mitochondrial deacetylase Sirt3 leading to hyperacetylation of mitochondrial proteins. There is likely a causative role. Indeed, genetic deletion of Sirt3 in mice promotes vascular dysfunction and hypertension. Sirt3 depletion promotes endothelial dysfunction, increases smooth muscle cell hypertrophy, instigates vascular inflammation, and induces age-dependent hypertension. Summary Sirt3 is critical for vascular cell homeostasis, however, multiple risk factors impair Sirt3 leading to mitochondrial dysfunction and vascular dysregulation which contribute to hypertension and end-organ injury. Targeting Sirt3 may represent novel therapeutic approach to improve treatment of vascular dysfunction and reduce hypertension.

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Mitochondrial Isolevuglandins Contribute to Vascular Oxidative Stress and Mitochondria-Targeted Scavenger of Isolevuglandins Reduces Mitochondrial Dysfunction and Hypertension

Cited by 23 publications

References 74 publications

Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

Disparate Roles of Oxidative Stress in Rostral Ventrolateral Medulla in Age-Dependent Susceptibility to Hypertension Induced by Systemic l-NAME Treatment in Rats

Mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension

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