PMID- 31852393
OWN - NLM
STAT- MEDLINE
DCOM- 20200727
LR  - 20210514
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 126
IP  - 4
DP  - 2020 Feb 14
TI  - Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension 
      While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular 
      Inflammation and Oxidative Stress.
PG  - 439-452
LID - 10.1161/CIRCRESAHA.119.315767 [doi]
AB  - RATIONALE: Hypertension represents a major risk factor for stroke, myocardial 
      infarction, and heart failure and affects 30% of the adult population. 
      Mitochondrial dysfunction contributes to hypertension, but specific mechanisms 
      are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the 
      regulation of metabolic and antioxidant functions which are associated with 
      hypertension, and cardiovascular disease risk factors diminish Sirt3 level. 
      OBJECTIVE: We hypothesized that reduced Sirt3 expression contributes to vascular 
      dysfunction in hypertension, but increased Sirt3 protects vascular function and 
      decreases hypertension. METHODS AND RESULTS: To test the therapeutic potential of 
      targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX 
      (Sirt3 overexpression), which protects from endothelial dysfunction, vascular 
      oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and 
      deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in 
      Sirt3(-/-) mice results in oxidative stress due to hyperacetylation of 
      mitochondrial superoxide dismutase (SOD2), increases HIF1alpha (hypoxia-inducible 
      factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, 
      increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM 
      [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], 
      and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell 
      infiltration in the kidney, reduces telomerase expression, and accelerates 
      vascular senescence and age-dependent hypertension; conversely, increased Sirt3 
      expression in Sirt3OX mice prevents these deleterious effects. The clinical 
      relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal 
      fat in patients with essential hypertension showing a 40% decrease in vascular 
      Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-kappaB 
      (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, 
      ICAM, and MCP1 levels in hypertensive subjects compared with normotensive 
      subjects. CONCLUSIONS: We suggest that Sirt3 depletion in hypertension promotes 
      endothelial dysfunction, vascular hypertrophy, vascular inflammation, and 
      end-organ damage. Our data support a therapeutic potential of targeting Sirt3 
      expression in vascular dysfunction and hypertension.
FAU - Dikalova, Anna E
AU  - Dikalova AE
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Pandey, Arvind
AU  - Pandey A
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Xiao, Liang
AU  - Xiao L
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Arslanbaeva, Liaisan
AU  - Arslanbaeva L
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Sidorova, Tatiana
AU  - Sidorova T
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Lopez, Marcos G
AU  - Lopez MG
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Billings, Frederic T 4th
AU  - Billings FT 4th
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Verdin, Eric
AU  - Verdin E
AD  - Buck Institute for Research on Aging, Novato, CA (E.V.).
FAU - Auwerx, Johan
AU  - Auwerx J
AD  - Ecole Polytechnique Federale de Lausanne, Switzerland (J.A.).
FAU - Harrison, David G
AU  - Harrison DG
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
FAU - Dikalov, Sergey I
AU  - Dikalov SI
AD  - From the Vanderbilt University Medical Center, Nashville, TN (A.E.D., A.P., L.X., 
      L.A., T.S., M.G.L., F.T.B., D.G.H., S.I.D.).
LA  - eng
GR  - R01 HL144943/HL/NHLBI NIH HHS/United States
GR  - R35 HL140016/HL/NHLBI NIH HHS/United States
GR  - R01 GM112871/GM/NIGMS NIH HHS/United States
GR  - K23 GM129662/GM/NIGMS NIH HHS/United States
GR  - R01 HL124116/HL/NHLBI NIH HHS/United States
GR  - UL1 RR024975/RR/NCRR NIH HHS/United States
GR  - P01 HL129941/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191219
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Mitochondrial Proteins)
RN  - 11128-99-7 (Angiotensin II)
RN  - 6E0A168OB8 (Desoxycorticosterone Acetate)
RN  - EC 3.5.1.- (Sirtuin 3)
SB  - IM
CIN - Circ Res. 2020 Feb 14;126(4):453-455. PMID: 32078456
CIN - Circ Res. 2020 Mar 27;126(7):e31-e32. PMID: 32213137
CIN - Circ Res. 2020 Mar 27;126(7):e33-e34. PMID: 32213139
MH  - Angiotensin II
MH  - Animals
MH  - Desoxycorticosterone Acetate
MH  - Endothelium, Vascular/metabolism/physiopathology
MH  - Essential Hypertension/chemically induced/genetics/*metabolism
MH  - Female
MH  - Heart/*physiopathology
MH  - Inflammation/genetics/*metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Mitochondria, Heart/genetics/metabolism
MH  - Mitochondrial Proteins/genetics/*metabolism
MH  - Myocardium/metabolism/pathology
MH  - *Oxidative Stress
MH  - Sirtuin 3/genetics/*metabolism
PMC - PMC7035170
MID - NIHMS1549189
OTO - NOTNLM
OT  - Sirtuin 3
OT  - acetylation
OT  - hypertension
OT  - mitochondria
OT  - oxidative stress
OT  - superoxide dismutase
EDAT- 2019/12/20 06:00
MHDA- 2020/07/28 06:00
PMCR- 2021/02/14
CRDT- 2019/12/20 06:00
PHST- 2019/12/20 06:00 [pubmed]
PHST- 2020/07/28 06:00 [medline]
PHST- 2019/12/20 06:00 [entrez]
PHST- 2021/02/14 00:00 [pmc-release]
AID - 10.1161/CIRCRESAHA.119.315767 [doi]
PST - ppublish
SO  - Circ Res. 2020 Feb 14;126(4):439-452. doi: 10.1161/CIRCRESAHA.119.315767. Epub 
      2019 Dec 19.