Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function

Margaret E. McCormick, Caitlin Collins, Catherine A. Makarewich, Zhongming Chen, Mauricio Rojas, Monte Willis, Steven R. Houser, Ellie Tzima

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

BACKGROUND: Dilated cardiomyopathy is characterized by impaired contractility of cardiomyocytes, ventricular chamber dilatation, and systolic dysfunction. Although mutations in genes expressed in the cardiomyocyte are the best described causes of reduced contractility, the importance of endothelial-cardiomyocyte communication for proper cardiac function is increasingly appreciated. In the present study, we investigate the role of the endothelial adhesion molecule platelet endothelial cell adhesion molecule (PECAM-1) in the regulation of cardiac function.

METHODS AND RESULTS: Using cell culture and animal models, we show that PECAM-1 expressed in endothelial cells (ECs) regulates cardiomyocyte contractility and cardiac function via the neuregulin-ErbB signaling pathway. Conscious echocardiography revealed left ventricular (LV) chamber dilation and systolic dysfunction in PECAM-1(-/-) mice in the absence of histological abnormalities or defects in cardiac capillary density. Despite deficits in global cardiac function, cardiomyocytes isolated from PECAM-1(-/-) hearts displayed normal baseline and isoproterenol-stimulated contractility. Mechanistically, absence of PECAM-1 resulted in elevated NO/ROS signaling and NRG-1 release from ECs, which resulted in augmented phosphorylation of its receptor ErbB2. Treatment of cardiomyocytes with conditioned media from PECAM-1(-/-) ECs resulted in enhanced ErbB2 activation, which was normalized by pre-treatment with an NRG-1 blocking antibody. To determine whether normalization of increased NRG-1 levels could correct cardiac function, PECAM-1(-/-) mice were treated with the NRG-1 blocking antibody. Echocardiography showed that treatment significantly improved cardiac function of PECAM-1(-/-) mice, as revealed by increased ejection fraction and fractional shortening.

CONCLUSIONS: We identify a novel role for PECAM-1 in regulating cardiac function via a paracrine NRG1-ErbB pathway. These data highlight the importance of tightly regulated cellular communication for proper cardiac function.

Original languageEnglish (US)
Pages (from-to)e001210
JournalJournal of the American Heart Association
Volume4
Issue number1
DOIs
StatePublished - Jan 19 2015
Externally publishedYes

Fingerprint

CD31 Antigens
Cardiac Myocytes
Communication
Blocking Antibodies
Endothelial Cells
Echocardiography
Dilatation
Neuregulins
Dilated Cardiomyopathy
Conditioned Culture Medium
Isoproterenol
Animal Models
Cell Culture Techniques
Phosphorylation

Keywords

  • cardiomyocyte
  • cardiomyopathy
  • endothelial cell
  • neuregulin‐1
  • PECAM‐1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function. / McCormick, Margaret E.; Collins, Caitlin; Makarewich, Catherine A.; Chen, Zhongming; Rojas, Mauricio; Willis, Monte; Houser, Steven R.; Tzima, Ellie.

In: Journal of the American Heart Association, Vol. 4, No. 1, 19.01.2015, p. e001210.

Research output: Contribution to journalArticle

McCormick, Margaret E. ; Collins, Caitlin ; Makarewich, Catherine A. ; Chen, Zhongming ; Rojas, Mauricio ; Willis, Monte ; Houser, Steven R. ; Tzima, Ellie. / Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function. In: Journal of the American Heart Association. 2015 ; Vol. 4, No. 1. pp. e001210.
@article{d24fe6bd5197479da12b3da2cc23f453,
title = "Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function",
abstract = "BACKGROUND: Dilated cardiomyopathy is characterized by impaired contractility of cardiomyocytes, ventricular chamber dilatation, and systolic dysfunction. Although mutations in genes expressed in the cardiomyocyte are the best described causes of reduced contractility, the importance of endothelial-cardiomyocyte communication for proper cardiac function is increasingly appreciated. In the present study, we investigate the role of the endothelial adhesion molecule platelet endothelial cell adhesion molecule (PECAM-1) in the regulation of cardiac function.METHODS AND RESULTS: Using cell culture and animal models, we show that PECAM-1 expressed in endothelial cells (ECs) regulates cardiomyocyte contractility and cardiac function via the neuregulin-ErbB signaling pathway. Conscious echocardiography revealed left ventricular (LV) chamber dilation and systolic dysfunction in PECAM-1(-/-) mice in the absence of histological abnormalities or defects in cardiac capillary density. Despite deficits in global cardiac function, cardiomyocytes isolated from PECAM-1(-/-) hearts displayed normal baseline and isoproterenol-stimulated contractility. Mechanistically, absence of PECAM-1 resulted in elevated NO/ROS signaling and NRG-1 release from ECs, which resulted in augmented phosphorylation of its receptor ErbB2. Treatment of cardiomyocytes with conditioned media from PECAM-1(-/-) ECs resulted in enhanced ErbB2 activation, which was normalized by pre-treatment with an NRG-1 blocking antibody. To determine whether normalization of increased NRG-1 levels could correct cardiac function, PECAM-1(-/-) mice were treated with the NRG-1 blocking antibody. Echocardiography showed that treatment significantly improved cardiac function of PECAM-1(-/-) mice, as revealed by increased ejection fraction and fractional shortening.CONCLUSIONS: We identify a novel role for PECAM-1 in regulating cardiac function via a paracrine NRG1-ErbB pathway. These data highlight the importance of tightly regulated cellular communication for proper cardiac function.",
keywords = "cardiomyocyte, cardiomyopathy, endothelial cell, neuregulin‐1, PECAM‐1",
author = "McCormick, {Margaret E.} and Caitlin Collins and Makarewich, {Catherine A.} and Zhongming Chen and Mauricio Rojas and Monte Willis and Houser, {Steven R.} and Ellie Tzima",
year = "2015",
month = "1",
day = "19",
doi = "10.1161/JAHA.114.001210",
language = "English (US)",
volume = "4",
pages = "e001210",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function

AU - McCormick, Margaret E.

AU - Collins, Caitlin

AU - Makarewich, Catherine A.

AU - Chen, Zhongming

AU - Rojas, Mauricio

AU - Willis, Monte

AU - Houser, Steven R.

AU - Tzima, Ellie

PY - 2015/1/19

Y1 - 2015/1/19

N2 - BACKGROUND: Dilated cardiomyopathy is characterized by impaired contractility of cardiomyocytes, ventricular chamber dilatation, and systolic dysfunction. Although mutations in genes expressed in the cardiomyocyte are the best described causes of reduced contractility, the importance of endothelial-cardiomyocyte communication for proper cardiac function is increasingly appreciated. In the present study, we investigate the role of the endothelial adhesion molecule platelet endothelial cell adhesion molecule (PECAM-1) in the regulation of cardiac function.METHODS AND RESULTS: Using cell culture and animal models, we show that PECAM-1 expressed in endothelial cells (ECs) regulates cardiomyocyte contractility and cardiac function via the neuregulin-ErbB signaling pathway. Conscious echocardiography revealed left ventricular (LV) chamber dilation and systolic dysfunction in PECAM-1(-/-) mice in the absence of histological abnormalities or defects in cardiac capillary density. Despite deficits in global cardiac function, cardiomyocytes isolated from PECAM-1(-/-) hearts displayed normal baseline and isoproterenol-stimulated contractility. Mechanistically, absence of PECAM-1 resulted in elevated NO/ROS signaling and NRG-1 release from ECs, which resulted in augmented phosphorylation of its receptor ErbB2. Treatment of cardiomyocytes with conditioned media from PECAM-1(-/-) ECs resulted in enhanced ErbB2 activation, which was normalized by pre-treatment with an NRG-1 blocking antibody. To determine whether normalization of increased NRG-1 levels could correct cardiac function, PECAM-1(-/-) mice were treated with the NRG-1 blocking antibody. Echocardiography showed that treatment significantly improved cardiac function of PECAM-1(-/-) mice, as revealed by increased ejection fraction and fractional shortening.CONCLUSIONS: We identify a novel role for PECAM-1 in regulating cardiac function via a paracrine NRG1-ErbB pathway. These data highlight the importance of tightly regulated cellular communication for proper cardiac function.

AB - BACKGROUND: Dilated cardiomyopathy is characterized by impaired contractility of cardiomyocytes, ventricular chamber dilatation, and systolic dysfunction. Although mutations in genes expressed in the cardiomyocyte are the best described causes of reduced contractility, the importance of endothelial-cardiomyocyte communication for proper cardiac function is increasingly appreciated. In the present study, we investigate the role of the endothelial adhesion molecule platelet endothelial cell adhesion molecule (PECAM-1) in the regulation of cardiac function.METHODS AND RESULTS: Using cell culture and animal models, we show that PECAM-1 expressed in endothelial cells (ECs) regulates cardiomyocyte contractility and cardiac function via the neuregulin-ErbB signaling pathway. Conscious echocardiography revealed left ventricular (LV) chamber dilation and systolic dysfunction in PECAM-1(-/-) mice in the absence of histological abnormalities or defects in cardiac capillary density. Despite deficits in global cardiac function, cardiomyocytes isolated from PECAM-1(-/-) hearts displayed normal baseline and isoproterenol-stimulated contractility. Mechanistically, absence of PECAM-1 resulted in elevated NO/ROS signaling and NRG-1 release from ECs, which resulted in augmented phosphorylation of its receptor ErbB2. Treatment of cardiomyocytes with conditioned media from PECAM-1(-/-) ECs resulted in enhanced ErbB2 activation, which was normalized by pre-treatment with an NRG-1 blocking antibody. To determine whether normalization of increased NRG-1 levels could correct cardiac function, PECAM-1(-/-) mice were treated with the NRG-1 blocking antibody. Echocardiography showed that treatment significantly improved cardiac function of PECAM-1(-/-) mice, as revealed by increased ejection fraction and fractional shortening.CONCLUSIONS: We identify a novel role for PECAM-1 in regulating cardiac function via a paracrine NRG1-ErbB pathway. These data highlight the importance of tightly regulated cellular communication for proper cardiac function.

KW - cardiomyocyte

KW - cardiomyopathy

KW - endothelial cell

KW - neuregulin‐1

KW - PECAM‐1

UR - http://www.scopus.com/inward/record.url?scp=85017330966&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017330966&partnerID=8YFLogxK

U2 - 10.1161/JAHA.114.001210

DO - 10.1161/JAHA.114.001210

M3 - Article

C2 - 25600142

AN - SCOPUS:85017330966

VL - 4

SP - e001210

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 1

ER -