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Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction.

ABSTRACT: Monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and the release from their splenic niche relies on angiotensin (Ang) II signaling.Because monocytes are centrally involved in tissue repair after ischemia, we hypothesized that early angiotensin-converting enzyme (ACE) inhibitor therapy impacts healing after myocardial infarction partly via effects on monocyte traffic.In a mouse model of permanent coronary ligation, enalapril arrested the release of monocytes from the splenic reservoir and consequently reduced their recruitment into the healing infarct by 45%, as quantified by flow cytometry of digested infarcts. Time-lapse intravital microscopy revealed that enalapril reduces monocyte motility in the spleen. In vitro migration assays and Western blotting showed that this was caused by reduced signaling through the Ang II type 1 receptor. We then studied the long-term consequences of blocked splenic monocyte release in atherosclerotic apolipoprotein (apo)E(-/-) mice, in which infarct healing is impaired because of excessive inflammation in the cardiac wound. Enalapril improved histologic healing biomarkers and reduced inflammation in infarcts measured by FMT-CT (fluorescence molecular tomography in conjunction with x-ray computed tomography) of proteolytic activity. ACE inhibition improved MRI-derived ejection fraction by 14% on day 21, despite initially comparable infarct size. In apoE(-/-) mice, ischemia/reperfusion injury resulted in larger infarct size and enhanced monocyte recruitment and was reversible by enalapril treatment. Splenectomy reproduced antiinflammatory effects of enalapril.This study suggests that benefits of early ACE inhibition after myocardial infarction can partially be attributed to its potent antiinflammatory impact on the splenic monocyte reservoir.

SUBMITTER: Leuschner F

PROVIDER: S-EPMC2992104 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction.

Leuschner Florian F Panizzi Peter P Chico-Calero Isabel I Lee Won Woo WW Ueno Takuya T Cortez-Retamozo Virna V Waterman Peter P Gorbatov Rostic R Marinelli Brett B Iwamoto Yoshiko Y Chudnovskiy Aleksey A Figueiredo Jose-Luiz JL Sosnovik David E DE Pittet Mikael J MJ Swirski Filip K FK Weissleder Ralph R Nahrendorf Matthias M

Circulation research 20101007 11

<h4>Rationale</h4>Monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and the release from their splenic niche relies on angiotensin (Ang) II signaling.<h4>Objective</h4>Because monocytes are centrally involved in tissue repair after ischemia, we hypothesized that early angiotensin-converting enzyme (ACE) inhibitor therapy impacts healing after myocardial infarction partly via effects on monocyte traffic.<h4>Methods and results</h4>In a mouse model of permanent c ...[more]

PMID: 20930148

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Project description:BackgroundTransforming growth factor beta (TGF-β)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-β-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis.MethodsMale C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery.ResultsSkeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-β and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure.ConclusionsACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.

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Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction.

Publications

Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction.

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