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Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac
Margaret E McCormick1, Caitlin Collins1, Catherine A Makarewich2
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.E.M.C., C.C., Z.C., E.T.).
Insights
Platelet endothelial cell adhesion molecule (PECAM-1) regulates cardiac function by modulating endothelial-cardiomyocyte communication. Blocking neuregulin-1 signaling in PECAM-1 deficient mice improved heart function, highlighting a novel therapeutic pathway.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Endothelial Function
Background:
- Dilated cardiomyopathy involves impaired cardiomyocyte contractility and ventricular dysfunction.
- Endothelial-cardiomyocyte communication is crucial for cardiac function, beyond cardiomyocyte-intrinsic defects.
- Platelet endothelial cell adhesion molecule (PECAM-1) is an endothelial adhesion molecule whose role in cardiac regulation is under investigation.
Purpose of the Study:
- To investigate the role of PECAM-1 in regulating cardiac function.
- To elucidate the molecular mechanisms by which PECAM-1 influences cardiomyocyte contractility and overall cardiac performance.
Main Methods:
- Utilized cell culture and PECAM-1 knockout (PECAM-1(-/-)) mouse models.
- Performed conscious echocardiography to assess cardiac function (left ventricular dilation, systolic dysfunction).
- Investigated signaling pathways including nitric oxide/reactive oxygen species (NO/ROS) and neuregulin-1 (NRG-1)/ErbB signaling.
- Administered NRG-1 blocking antibodies to PECAM-1(-/-) mice to assess therapeutic potential.
Main Results:
- PECAM-1(-/-) mice exhibited left ventricular dilation and systolic dysfunction without histological changes or altered capillary density.
- Absence of PECAM-1 led to increased NO/ROS signaling and NRG-1 release from endothelial cells, augmenting ErbB2 phosphorylation.
- Treatment with an NRG-1 blocking antibody significantly improved cardiac function in PECAM-1(-/-) mice, increasing ejection fraction and fractional shortening.
Conclusions:
- PECAM-1 plays a novel role in regulating cardiac function through a paracrine NRG1-ErbB signaling pathway.
- This study underscores the critical importance of intercellular communication for maintaining proper cardiac homeostasis.
- Targeting the NRG1-ErbB pathway represents a potential therapeutic strategy for cardiac dysfunction associated with altered PECAM-1 signaling.
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.
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