PMID- 34840266
OWN - NLM
STAT- MEDLINE
DCOM- 20220429
LR  - 20230911
IS  - 1533-4023 (Electronic)
IS  - 0160-2446 (Linking)
VI  - 79
IP  - 3
DP  - 2022 Mar 1
TI  - Pharmacological Inhibition of Mammalian Target of Rapamycin Attenuates 
      Deoxycorticosterone Acetate Salt-Induced Hypertension and Related 
      Pathophysiology: Regulation of Oxidative Stress, Inflammation, and Cardiovascular 
      Hypertrophy in Male Rats.
PG  - 355-367
LID - 10.1097/FJC.0000000000001187 [doi]
AB  - The present study aimed to explore the contribution of mammalian target of 
      rapamycin (mTOR) in deoxycorticosterone acetate (DOCA) salt-induced hypertension 
      and related pathophysiological changes in cardiovascular and renal tissues. DOCA 
      salt loading resulted in an increase in systolic blood pressure, diastolic blood 
      pressure, and mean blood pressure along with the activity of ribosomal protein 
      S6, the effector protein of mTOR. Treatment with rapamycin, the selective 
      inhibitor of mTOR, initiated at the fourth week of DOCA- salt administration 
      normalized the systolic blood pressure and attenuated ribosomal protein S6 
      activity in the heart, aorta, and kidney. Cardiac and vascular hypertrophy, 
      oxidative stress, and infiltration of macrophages (CD68+), the marker of 
      inflammation, were also reduced in rapamycin-treated, DOCA-salt, hypertensive 
      rats. In addition, renal hypertrophy and dysfunction were also reduced with 
      rapamycin-treated hypertensive rats. Moreover, these pathophysiological changes 
      in DOCA-salt hypertensive rats were associated with increased NADPH oxidase (NOX) 
      activity, gp91phox (formerly NOX2) expression, ERK1/2, and p38 MAPK activities in 
      the heart, aorta, and kidney were minimized by rapamycin. These data indicate 
      that mTOR plays an important role in regulating blood pressure and the 
      development of cardiovascular and renal pathophysiological changes, most likely 
      due to increased NOX expression/activity, ERK1/2, and p38 MAPK activity with 
      macrophages infiltration in the heart, kidney, and aorta. Pharmacological 
      inhibition of mTOR and related signaling pathways could serve as a novel target 
      for the treatment of hypertension.
CI  - Copyright (c) 2022 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Temiz-Resitoglu, Meryem
AU  - Temiz-Resitoglu M
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Guden, Demet S
AU  - Guden DS
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Senol, Sefika P
AU  - Senol SP
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Vezir, Ozden
AU  - Vezir O
AD  - Department of Cardiovascular Surgery, Mersin State Hospital, Mersin, Turkey.
FAU - Sucu, Nehir
AU  - Sucu N
AD  - Departments of Cardiovascular Surgery; and.
FAU - Kibar, Deniz
AU  - Kibar D
AD  - Histology and Embryology, Faculty of Medicine, Mersin University, Mersin, Turkey 
      ; and.
FAU - Yilmaz, Sakir N
AU  - Yilmaz SN
AD  - Histology and Embryology, Faculty of Medicine, Mersin University, Mersin, Turkey 
      ; and.
FAU - Tunctan, Bahar
AU  - Tunctan B
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Malik, Kafait U
AU  - Malik KU
AD  - Department of Pharmacology, College of Medicine, University of Tennessee, Center 
      for Health Sciences, Memphis, TN.
FAU - Sahan-Firat, Seyhan
AU  - Sahan-Firat S
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cardiovasc Pharmacol
JT  - Journal of cardiovascular pharmacology
JID - 7902492
RN  - 0 (Acetates)
RN  - 0 (Ribosomal Protein S6)
RN  - 6E0A168OB8 (Desoxycorticosterone Acetate)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Acetates/adverse effects
MH  - Animals
MH  - Blood Pressure
MH  - *Desoxycorticosterone Acetate/adverse effects
MH  - *Hypertension/chemically induced/drug therapy/metabolism
MH  - Hypertrophy
MH  - Inflammation
MH  - Male
MH  - Mammals/metabolism
MH  - Oxidative Stress
MH  - Rats
MH  - Ribosomal Protein S6/metabolism
MH  - Sirolimus/adverse effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
COIS- The authors report no conflicts of interest.
EDAT- 2021/11/30 06:00
MHDA- 2022/04/30 06:00
CRDT- 2021/11/29 06:18
PHST- 2021/06/01 00:00 [received]
PHST- 2021/11/04 00:00 [accepted]
PHST- 2021/11/30 06:00 [pubmed]
PHST- 2022/04/30 06:00 [medline]
PHST- 2021/11/29 06:18 [entrez]
AID - 00005344-202203000-00014 [pii]
AID - 10.1097/FJC.0000000000001187 [doi]
PST - ppublish
SO  - J Cardiovasc Pharmacol. 2022 Mar 1;79(3):355-367. doi: 
      10.1097/FJC.0000000000001187.