PMID- 30612527
OWN - NLM
STAT- MEDLINE
DCOM- 20191219
LR  - 20200309
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 124
IP  - 5
DP  - 2019 Mar
TI  - Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin 
      II-Induced Hypertension.
PG  - 727-736
LID - 10.1161/CIRCRESAHA.118.313882 [doi]
AB  - RATIONALE: Increased microglial activation and neuroinflammation within autonomic 
      brain regions have been implicated in sustained hypertension, and their 
      inhibition by minocycline-an anti-inflammatory antibiotic-produces beneficial 
      effects. These observations led us to propose a dysfunctional brain-gut 
      communication hypothesis for hypertension. However, it has been difficult to 
      reconcile whether an anti-inflammatory or antimicrobial action is the primary 
      beneficial effect of minocycline in hypertension. Accordingly, we utilized 
      chemically modified tetracycline-3 (CMT-3)-a derivative of tetracycline that has 
      potent anti-inflammatory activity-to address this question. OBJECTIVE: Test the 
      hypothesis that central administration of CMT-3 would inhibit microglial 
      activation, attenuate neuroinflammation, alter selective gut microbial 
      communities, protect the gut wall from developing hypertension-associated 
      pathology, and attenuate hypertension. METHODS AND RESULTS: Rats were implanted 
      with radiotelemetry devices for recording mean arterial pressure. Ang II 
      (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce 
      hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 
      intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also 
      investigated in SHR (spontaneously hypertensive rats). Physiological, 
      pathological, immunohistological parameters, and fecal microbiota were analyzed. 
      Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in 
      number of microglia, their activation, and proinflammatory cytokines in the 
      paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 
      attenuated increased mean arterial pressure, normalized sympathetic activity, and 
      left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, 
      CMT-3 beneficially restored certain gut microbial communities altered by Ang II 
      and attenuated pathological alterations in gut wall. CONCLUSIONS: These 
      observations demonstrate that inhibition of microglial activation alone was 
      sufficient to induce significant antihypertensive effects. This was associated 
      with unique changes in gut microbial communities and profound attenuation of gut 
      pathology. They suggest, for the first time, a link between microglia and certain 
      microbial communities that may have implications for treatment of hypertension.
FAU - Sharma, Ravindra K
AU  - Sharma RK
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Yang, Tao
AU  - Yang T
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Oliveira, Aline C
AU  - Oliveira AC
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Lobaton, Gilberto O
AU  - Lobaton GO
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Aquino, Victor
AU  - Aquino V
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Kim, Seungbum
AU  - Kim S
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Richards, Elaine M
AU  - Richards EM
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Pepine, Carl J
AU  - Pepine CJ
AD  - Department of Medicine (C.J.P.), College of Medicine, University of Florida, 
      Gainesville.
FAU - Sumners, Colin
AU  - Sumners C
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
FAU - Raizada, Mohan K
AU  - Raizada MK
AD  - From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., 
      G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of 
      Florida, Gainesville.
LA  - eng
GR  - R01 HL033610/HL/NHLBI NIH HHS/United States
GR  - R01 HL102033/HL/NHLBI NIH HHS/United States
GR  - R01 HL132448/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Tetracyclines)
RN  - 0 (tetracycline CMT-3)
RN  - 11128-99-7 (Angiotensin II)
SB  - IM
CIN - Circ Res. 2019 Mar;124(5):671-673. PMID: 30817265
MH  - Angiotensin II
MH  - Animals
MH  - Anti-Bacterial Agents/administration & dosage
MH  - Anti-Inflammatory Agents/administration & dosage
MH  - Antihypertensive Agents/*administration & dosage
MH  - Arterial Pressure/drug effects
MH  - Autonomic Nervous System/drug effects/physiopathology
MH  - Disease Models, Animal
MH  - Gastrointestinal Microbiome/*drug effects
MH  - Hypertension/*drug therapy/microbiology/pathology/physiopathology
MH  - Infusions, Intraventricular
MH  - Intestines/*drug effects/innervation/microbiology/pathology
MH  - Male
MH  - Microglia/*drug effects/pathology
MH  - Paraventricular Hypothalamic Nucleus/*drug effects/pathology/physiopathology
MH  - Rats, Inbred SHR
MH  - Rats, Inbred WKY
MH  - Tetracyclines/*administration & dosage
PMC - PMC6395495
MID - NIHMS1518223
OTO - NOTNLM
OT  - CMT-3
OT  - angiotensin II
OT  - gut dysbiosis ◼ hypertension
OT  - microglia
OT  - neuroinflammation ◼ paraventricular hypothalamic nucleus
OT  - tetracycline
EDAT- 2019/01/08 06:00
MHDA- 2019/12/20 06:00
PMCR- 2020/03/01
CRDT- 2019/01/08 06:00
PHST- 2019/01/08 06:00 [pubmed]
PHST- 2019/12/20 06:00 [medline]
PHST- 2019/01/08 06:00 [entrez]
PHST- 2020/03/01 00:00 [pmc-release]
AID - 10.1161/CIRCRESAHA.118.313882 [doi]
PST - ppublish
SO  - Circ Res. 2019 Mar;124(5):727-736. doi: 10.1161/CIRCRESAHA.118.313882.