Abstract P080: Mutation Of Lysine 68 To Arginine Mimics Deacetylation Of Mitochondrial Superoxide Dismutase, Protects From Vascular Oxidative Stress And Attenuates Angiotensin II-Induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Anna Dikalova ◽  
Liliya Tkachuk ◽  
Marcos G Lopez ◽  
Frederic T Billings ◽  
Sergey I Dikalov
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Superoxide Dismutase ◽  
Angiotensin Ii ◽  
Wild Type ◽  
Mitochondrial Superoxide ◽  
Induced Hypertension ◽  
Lysine Residues ◽  
Vascular Oxidative Stress

By recent guidelines, almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. We found that hypertension is associated with inactivation of key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to acetylation of lysine residues at the catalytic center. The role of specific SOD2 lysine residues in hypertension, however, has not been defined. We proposed that inactivation of key intrinsic antioxidant, SOD2, in hypertension is linked to acetylation of Lysine 68, and mutation of K68 to Arginine mimics SOD2 deacetylation, inhibits vascular oxidative stress and attenuates angiotensin II-induced hypertension. To test this hypothesis, we have investigated SOD2 acetylation in arterioles from patients with essential hypertension and developed a new deacetylation mimic SOD2 mutant K68R mice (SOD2-K68R). Western blot analysis of arterioles isolated from human mediastinal fat showed 3-fold increase in SOD2 acetylation in hypertensive patients compared with normotensive subjects while SOD2 levels were not affected. To define the functional significance of K68 acetylation we performed studies in vivo in SOD2-K68R mice using angiotensin II model of vascular dysfunction and hypertension. Angiotensin II infusion in wild-type C57Bl/6J mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. Mutation of Lysine 68 to Arginine in SOD2-K68R mice completely prevented the increase in mitochondrial superoxide and significantly attenuated the angiotensin II induced hypertension (135 mm Hg). Angiotensin II and TNFα co-operatively induce SOD2 acetylation and hypertension. Treatment of wild-type aortas with angiotensin II and TNFα in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. These data support an important role of SOD2-K68 acetylation in hypertension, and strategies to reduce mitochondrial acetylation may have therapeutic potential.

Abstract 15061: Essential Hypertension is Linked to Acetylation of Mitochondrial Superoxide Dismutase and Deacetylation Mimetic Mutation of Lysine 68 to Arginine Protects From Oxidative Stress and Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anna Dikalova ◽  
Liliya Tkachuk ◽  
Marcos G Lopez ◽  
Frederic T Billings ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Superoxide Dismutase ◽  
Essential Hypertension ◽  
Angiotensin Ii ◽  
Wild Type ◽  
Mitochondrial Superoxide ◽  
Induced Hypertension ◽  
Lysine Residues

Almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. We found that hypertension is associated with inactivation of key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to acetylation of lysine residues at the catalytic center. The role of specific SOD2 lysine residues in hypertension, however, has not been defined. Hypothesis: We proposed that inactivation of key intrinsic antioxidant, SOD2, in hypertension is linked to acetylation of Lysine 68, and mutation of K68 to Arginine mimics SOD2 deacetylation, inhibits vascular oxidative stress and attenuates angiotensin II-induced hypertension. To test this hypothesis, we have investigated SOD2 acetylation in arterioles from patients with essential hypertension and developed a new deacetylation mimic SOD2 mutant K68R mice (SOD2-K68R). Western blot of arterioles isolated from human mediastinal fat showed 3-fold increase in SOD2 acetylation in hypertensive patients compared with normotensive subjects while SOD2 levels were not affected. To define the functional significance of K68 acetylation we performed studies in vivo in SOD2-K68R mice using angiotensin II model of vascular dysfunction and hypertension. Angiotensin II infusion in wild-type C57Bl/6J mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. Mutation of Lysine 68 to Arginine in SOD2-K68R mice completely prevented the increase in mitochondrial superoxide and significantly attenuated the angiotensin II induced hypertension (135 mm Hg). Angiotensin II and TNFα co-operatively induce SOD2 acetylation and hypertension. Treatment of wild-type aortas with angiotensin II and TNFα in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. Conclusions: These data support an important role of SOD2-K68 acetylation in hypertension and targeting Sirt3-mediated deacetylation of SOD2 may have therapeutic potential.

Abstract MP01: Deacetylation Of Mitochondrial Cyclophilin D K166 Inhibits Cytokine-induced Oxidative Stress And Attenuates Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sergey I Dikalov ◽  
Vladimir Mayorov ◽  
Daniel Fehrenbach ◽  
Mingfang Ao ◽  
Alexander Panov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Vascular Function ◽  
Organ Damage ◽  
Cyclophilin D ◽  
Wild Type ◽  
End Organ Damage ◽  
Mitochondrial Superoxide ◽  
Vascular Oxidative Stress

We have previously reported that depletion Cyclophilin D (CypD), a regulatory subunit of mitochondrial permeability transition pore, improves vascular function and attenuates hypertension, however, specific regulation of CypD in hypertension is not clear. Analysis of human arterioles from hypertensive patients did not reveal alterations in CypD levels but showed 3-fold increase in CypD acetylation. We hypothesized that CypD-K166 acetylation promotes vascular oxidative stress and hypertension, and measures to reduce CypD acetylation can improve vascular function and reduce hypertension. Essential hypertension and animal models of hypertension are linked to inactivation of mitochondrial deacetylase Sirt3 by highly reactive lipid oxidation products, isolevuglandins (isoLGs), and supplementation of mice with mitochondria targeted scavenger of isoLGs, mito2HOBA, improves CypD deacetylation. To test the specific role of CypD-K166 acetylation, we developed CypD-K166R deacetylation mimic mutant mice. Mitochondrial respiration, vascular function and systolic blood pressure in CypD-K166R mice was similar to wild-type C57Bl/6J mice. Meanwhile, angiotensin II-induced hypertension was substantially attenuated in CypD-K166R mice (144 mmHg) compared with wild-type mice (161 mmHg). Angiotensin II infusion in wild-type mice significantly increased mitochondrial superoxide, impaired endothelial dependent relaxation, and reduced the level of endothelial nitric oxide which was prevented in angiotensin II-infused CypD-K166R mice. Hypertension is linked to increased levels of inflammatory cytokines TNFα and IL-17A promoting vascular oxidative stress and end-organ damage. We have tested if CypD-K166R mice are protected from cytokine-induced oxidative stress. Indeed, ex vivo incubation of aorta with the mixture of angiotensin II, TNFα and IL-17A (24 hours) increased mitochondrial superoxide by 2-fold in wild-type aortas which was abrogated in CypD-K166R mice. These data support the pathophysiological role of CypD acetylation in inflammation, oxidative stress and hypertensive end-organ damage. We propose that targeting CypD acetylation may have therapeutic potential in treatment of vascular dysfunction and hypertension.

Abstract 058: Sirt3 Impairment and SOD2 Hyperacetylation Drive Vascular Oxidative Stress and Hypertension

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Rafal Nazarewicz ◽  
Anna Dikalova ◽  
Joshua P Fessel ◽  
Hana Itani ◽  
William McMaster ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Inflammatory Cells ◽  
Blood Pressure Elevation ◽  
Aortic Endothelial Cells ◽  
Mitochondrial Superoxide ◽  
Induced Hypertension ◽  
Vascular Oxidative Stress ◽  
Sirt3 Expression

Aging is associated with increased incidence of hypertension and a decline of the mitochondrial energy regulator deacetylase Sirt3. A major mitochondrial antioxidant enzyme, SOD2, is inhibited by acetylation and its deacetylation by Sirt3 restores SOD2 activity. We hypothesized that loss of Sirt3 activity increases vascular oxidative stress due to SOD2 hyperacetylation and that this promotes hypertension. The combination of angiotensin II and TNFα, which is produced by inflammatory cells in hypertension, synergistically reduced Sirt3 expression, induced SOD2 acetylation and increased mitochondrial superoxide (O 2 • - ) in human aortic endothelial cells (HAEC). mitoEbselen, which scavenges mitochondrial H 2 O 2 , prevented SOD2 acetylation in HAEC and normalized mitochondrial O 2 • - suggesting redox-dependent modulation of Sirt3. In intact mice, chronic AngII infusion (490 ng/kg/min) reduced vascular Sirt3 expression by 20%, caused Sirt3 S-glutathionylation, SOD2 hyperacetylation and reduced SOD2 activity by 42%. Mice transgenic for mitochondria-targeted catalase exhibited reduced Sirt3 S-glutathionylation, no SOD2 hyperacetylation, maintenance of SOD2 activity and no increase in mitochondrial O 2 • - . The functional role of Sirt3 S-glutathionylation was further supported by mitoEbselen treatment of WT and Sirt3 -/- mice after the onset of AngII-induced hypertension. mitoEbselen reduced vascular oxidative stress and hypertension in WT but not in Sirt3 -/- mice. In Sirt3 -/- mice, low dose AngII (200 ng/kg/min) caused greater hypertension (150 mm Hg) than in WT (128 mm Hg, P<0.01) and AngII-infused Sirt3 -/- mice produced less nitric oxide that WT, as detected by electron spin resonance (70 pmol/aorta vs 110 WT+AngII, P< 0.01). We further showed that treatment with the mitochondria targeted SOD2 mimetic mitoTEMPO, initiated after the onset of AngII-induced hypertension lowered blood pressure and improved vasodilatation in both WT and Sirt3 -/- mice, further supporting a role of mitochondrial O 2 • - in hypertension. These data indicate that reduced Sirt3 activity occurs in hypertension due to S-glutathionylation and that this leads to SOD2 hyperacetylation and inactivation, promoting vascular oxidative stress and blood pressure elevation.

scholarly journals Regulation of Biogenesis and Fusion/Fission Processes of Vascular Mitochondria In Aldosterone-Induced Hypertension

2018 ◽  
Vol 10 (1) ◽  
pp. 76-85
Author(s):  
Elena Olivares-Álvaro ◽  
María Belén Ruiz-Roso ◽  
Mercedes Klett-Mingo ◽  
Sandra Ballesteros ◽  
Ricardo Gredilla ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Wistar Rats ◽  
Mitochondrial Alterations ◽  
Induced Hypertension ◽  
Male Wistar Rats ◽  
Vascular Oxidative Stress

Background:Aldosterone plays a key role in the development of endothelial dysfunction and hypertension. The regulation of biogenesis and fusion/fission processes of vascular mitochondria has not been examined in aldosterone-induced hypertension. Thereby, we sought to explore in greater depth the role of aldosterone in mitochondrial biogenesis and fusion/fission processes in hypertension and the associated increases in oxidative stress.Methods:Male Wistar rats received aldosterone (1mg/Kg/day) + 1% NaCl as drinking water for 3 weeks.Results:Systolic blood pressure was elevated (p<0.05) in aldosterone-treated rats. eNOS and p-eNOSSer1177protein expression was down regulated (p<0.05) and NADPH oxidase subunit p22phox expression was increased (p<0.05) in aldosterone-treated rats. Expression of mitochondrial biogenesis proteins SIRT1, PGC1α, PPARγ, and TFAM decreased (p<0.05) in aldosterone-treated rats. Protein expression of vascular DRP1, OMA1 and S-OPA1 up regulated (p<0.05) in aldosterone-treated rats. MFN1 and L-OPA1 (p<0.05) decreased in aldosterone-treated animals.Conclusion:The results showed that, in aldosterone-treated rats, hypertension is likely associated with increased oxidative stress in the aorta and with changes in the regulation of two key mitochondrial processes such as biogenesis and fusion/fission processes. The overall mitochondrial alterations observed in the study may play a role in aldosterone-derived vascular oxidative stress and hypertension.

scholarly journals Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Xiao Chun Li ◽  
Ana Paula Oliveira Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Xu Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Normal Blood ◽  
Ang Ii ◽  
Normal Blood Pressure ◽  
Wild Type ◽  
Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

scholarly journals Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

2019 ◽  
Vol 51 (4) ◽  
pp. 97-108 ◽  
Author(s):  
Xiao C. Li ◽  
Xiaowen Zheng ◽  
Xu Chen ◽  
Chunling Zhao ◽  
Dongmin Zhu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Blood Pressure Homeostasis ◽  
Induced Hypertension ◽  
Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis

2002 ◽  
Vol 282 (4) ◽  
pp. L719-L726 ◽  
Author(s):  
Russell P. Bowler ◽  
Mike Nicks ◽  
Karrie Warnick ◽  
James D. Crapo
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Immunohistochemical Staining ◽  
Extracellular Superoxide Dismutase ◽  
Wild Type ◽  
Injured Lung ◽  
Intracellular Oxidative Stress

Bleomycin administration results in well-described intracellular oxidative stress that can lead to pulmonary fibrosis. The role of alveolar interstitial antioxidants in this model is unknown. Extracellular superoxide dismutase (EC-SOD) is the primary endogenous extracellular antioxidant enzyme and is abundant in the lung. We hypothesized that EC-SOD plays an important role in attenuating bleomycin-induced lung injury. Two weeks after intratracheal bleomycin administration, we found that wild-type mice induced a 106 ± 25% increase in lung EC-SOD. Immunohistochemical staining revealed that a large increase in EC-SOD occurred in injured lung. Using mice that overexpress EC-SOD specifically in the lung, we found a 53 ± 14% reduction in bleomycin-induced lung injury assessed histologically and a 17 ± 6% reduction in lung collagen content 2 wk after bleomycin administration. We conclude that EC-SOD plays an important role in reducing the magnitude of lung injury from extracellular free radicals after bleomycin administration.

scholarly journals Angiotensin II acts through the angiotensin 1a receptor to upregulate pendrin

2011 ◽  
Vol 301 (6) ◽  
pp. F1314-F1325 ◽  
Author(s):  
Jill W. Verlander ◽  
Seongun Hong ◽  
Vladimir Pech ◽  
James L. Bailey ◽  
Diana Agazatian ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Membrane ◽  
Angiotensin Ii ◽  
Pressor Response ◽  
Angiotensin Receptors ◽  
Apical Plasma Membrane ◽  
Protein Abundance ◽  
Wild Type ◽  
Induced Hypertension

Pendrin is an anion exchanger expressed in the apical regions of B and non-A, non-B intercalated cells. Since angiotensin II increases pendrin-mediated Cl− absorption in vitro, we asked whether angiotensin II increases pendrin expression in vivo and whether angiotensin-induced hypertension is pendrin dependent. While blood pressure was similar in pendrin null and wild-type mice under basal conditions, following 2 wk of angiotensin II administration blood pressure was 31 mmHg lower in pendrin null than in wild-type mice. Thus pendrin null mice have a blunted pressor response to angiotensin II. Further experiments explored the effect of angiotensin on pendrin expression. Angiotensin II administration shifted pendrin label from the subapical space to the apical plasma membrane, independent of aldosterone. To explore the role of the angiotensin receptors in this response, pendrin abundance and subcellular distribution were examined in wild-type, angiotensin type 1a (Agtr1a) and type 2 receptor (Agtr2) null mice given 7 days of a NaCl-restricted diet (< 0.02% NaCl). Some mice received an Agtr1 inhibitor (candesartan) or vehicle. Both Agtr1a gene ablation and Agtr1 inhibitors shifted pendrin label from the apical plasma membrane to the subapical space, independent of the Agtr2 or nitric oxide (NO). However, Agtr1 ablation reduced pendrin protein abundance through the Agtr2 and NO. Thus angiotensin II-induced hypertension is pendrin dependent. Angiotensin II acts through the Agtr1a to shift pendrin from the subapical space to the apical plasma membrane. This Agtr1 action may be blunted by the Agtr2, which acts through NO to reduce pendrin protein abundance.

Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence

2007 ◽  
Vol 102 (1) ◽  
pp. 255-260 ◽  
Author(s):  
Bernardo Rodriguez-Iturbe ◽  
Lili Sepassi ◽  
Yasmir Quiroz ◽  
Zhenmin Ni ◽  
Nosratola D. Vaziri
Keyword(s):  
Oxidative Stress ◽  
Glomerular Sclerosis ◽  
Tubular Damage ◽  
Wild Type ◽  
Mitochondrial Superoxide ◽  
Show Evidence ◽  
Blood Pressures ◽  
Renal Senescence ◽  
Salt Sensitive Hypertension

Mitochondria are the major source of superoxide (O2−) in the aerobic organisms. O2− produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2−/−) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2+/−) show evidence of O2−-induced mitochondrial damage resembling cell senescence. Since earlier studies have provided compelling evidence for the role of oxidative stress and tubulointerstitial inflammation in the pathogenesis of hypertension, we tested the hypothesis that partial SOD2 deficiency may result in hypertension. Wild-type (SOD2+/+) and partial SOD2-deficient (SOD2+/−) mice had similar blood pressures at 6–7 mo of age, but at 2 yr SOD2+/− mice had higher blood pressure. Oxidative stress, renal interstitial T-cell and macrophage infiltration, tubular damage, and glomerular sclerosis were all significantly increased in 2-yr-old SOD2+/− mice. High-salt diet induced hypertension in 6-mo-old SOD2-deficient mice but not in wild-type mice. In conclusion, partial SOD2 deficiency results in oxidative stress and renal interstitial inflammation, changes compatible with accelerated renal senescence and salt-sensitive hypertension. These findings are consistent with the pattern described in numerous other models of salt-sensitive hypertension and resemble that commonly seen in elderly humans.

Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Germán E González ◽  
Nour-Eddine Rhaleb ◽  
Xiao- P Yang ◽  
Oscar A Carretero
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Carbohydrate Binding ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Galectin 3

We previously described that chronic infusion with Angiotensin II (Ang II) increases cardiac Galectin-3 (Gal-3) expression, a carbohydrate-binding lectin present on macrophages. Also, Gal-3 was proposed to be a powerful predictor for mortality in patients with heart failure. Nevertheless, the role of Gal-3 in the pathogenesis of end organ damage (EOD) in hypertension is unknown. Here, we hypothesized that in Ang II-induced hypertension, genetic deletion of Gal-3 prevents innate immunity, EOD, and left ventricular (LV) dysfunction. Male C57 and Gal-3 KO mice were infused with vehicle (V) or Ang II (90 ng/min; s.c.) for 8 weeks and divided into: 1) C57 + V; 2) Gal-3 KO + V; 3) C57 + Ang II and 4) Gal-3 KO + Ang II. Systolic blood pressure (SBP) was measured by plestimography weekly. At 8 week, we evaluated 1) LV ejection fraction (EF) by echocardiography; 2) cardiac hypertrophy by LV weight/tibia length; 3) cardiac fibrosis by picrosirius red staining; 4) infiltrated macrophages by CD68+ staining; 5) ICAM-1 protein expression by Western blot; and 6) serum interleukin (IL)-6 by ELISA. We found that despite a similar increase in SBP and LV hypertrophy in both strains on Ang II, Gal-3 KO mice had better reserved EF and decreased inflammatory and fibrotic responses (see Table). Results: (MEAN ± SEM at 8 w) *p<0.05 C57+Ang II and Gal-3 KO+Ang II vs C57+V; ‡ p<0.05 Gal-3 KO+Ang II vs C57+Ang II. Conclusion: In Ang II-induced hypertension, deletion of Gal-3 prevents EOD and LV systolic dysfunction without altering blood pressure and LV hypertrophy. This study indicates that the deleterious effects of Ang II could be in part mediated by Gal-3, which enhanced inflammation and fibrosis.

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