Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice

Zhi Dong Ge; Riley M. Boyd; Connor Lantz; Edward B. Thorp; Joseph M. Forbess

doi:10.1016/j.xjon.2022.02.027

Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice

Zhi Dong Ge, Riley M. Boyd, Connor Lantz, Edward B. Thorp, Joseph M. Forbess^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCII^loLyve1+TimD4+ (Major histocompatibility complex class II^low lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental–cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCII^loLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy.

Original language	English (US)
Pages (from-to)	222-242
Number of pages	21
Journal	JTCVS Open
Volume	10
DOIs	https://doi.org/10.1016/j.xjon.2022.02.027
State	Published - Jun 2022

Funding

This study was supported by the Stanley Manne Heart Center and the Department of Surgery from Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, and the National Institutes of Health research grants R01HL122309 and R01HL139812 from the United States Public Health Services, Bethesda, Maryland.The authors thank Dr Matthew DeBerge at Northwestern University, Dr Ashok K. Singh at the University of Illinois at Chicago, the NUSeq core, and the Nanostring Technologies POP laboratory staff for their technical support in flow cytometric analysis of mouse hearts, treatment of the greater omentum, RNA quality control analyses, and expression panel analysis, respectively. This study was supported by the Stanley Manne Heart Center and the Department of Surgery from Ann & Robert H. Lurie Children’s Hospital of Chicago , Chicago, Illinois, and the National Institutes of Health research grants R01HL122309 and R01HL139812 from the United States Public Health Services , Bethesda, Maryland.

Keywords

angiogenesis
cardiac hypertrophy
cardio-omentopexy
macrophages

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Pulmonary and Respiratory Medicine
Surgery

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10.1016/j.xjon.2022.02.027

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title = "Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice",

abstract = "Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental–cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy.",

keywords = "angiogenesis, cardiac hypertrophy, cardio-omentopexy, macrophages",

author = "Ge, {Zhi Dong} and Boyd, {Riley M.} and Connor Lantz and Thorp, {Edward B.} and Forbess, {Joseph M.}",

note = "Funding Information: This study was supported by the Stanley Manne Heart Center and the Department of Surgery from Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, and the National Institutes of Health research grants R01HL122309 and R01HL139812 from the United States Public Health Services, Bethesda, Maryland.The authors thank Dr Matthew DeBerge at Northwestern University, Dr Ashok K. Singh at the University of Illinois at Chicago, the NUSeq core, and the Nanostring Technologies POP laboratory staff for their technical support in flow cytometric analysis of mouse hearts, treatment of the greater omentum, RNA quality control analyses, and expression panel analysis, respectively. Funding Information: This study was supported by the Stanley Manne Heart Center and the Department of Surgery from Ann & Robert H. Lurie Children{\textquoteright}s Hospital of Chicago , Chicago, Illinois, and the National Institutes of Health research grants R01HL122309 and R01HL139812 from the United States Public Health Services , Bethesda, Maryland. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jun,

doi = "10.1016/j.xjon.2022.02.027",

language = "English (US)",

volume = "10",

pages = "222--242",

journal = "JTCVS Open",

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T1 - Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice

AU - Ge, Zhi Dong

AU - Boyd, Riley M.

AU - Lantz, Connor

AU - Thorp, Edward B.

AU - Forbess, Joseph M.

N1 - Funding Information: This study was supported by the Stanley Manne Heart Center and the Department of Surgery from Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, and the National Institutes of Health research grants R01HL122309 and R01HL139812 from the United States Public Health Services, Bethesda, Maryland.The authors thank Dr Matthew DeBerge at Northwestern University, Dr Ashok K. Singh at the University of Illinois at Chicago, the NUSeq core, and the Nanostring Technologies POP laboratory staff for their technical support in flow cytometric analysis of mouse hearts, treatment of the greater omentum, RNA quality control analyses, and expression panel analysis, respectively. Funding Information: This study was supported by the Stanley Manne Heart Center and the Department of Surgery from Ann & Robert H. Lurie Children’s Hospital of Chicago , Chicago, Illinois, and the National Institutes of Health research grants R01HL122309 and R01HL139812 from the United States Public Health Services , Bethesda, Maryland. Publisher Copyright: © 2022 The Author(s)

PY - 2022/6

Y1 - 2022/6

N2 - Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental–cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy.

AB - Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental–cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy.

KW - angiogenesis

KW - cardiac hypertrophy

KW - cardio-omentopexy

KW - macrophages

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Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice

Abstract

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