Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction

Cimini, Maria; Garikipati, Venkata Naga Srikanth; Lucia, Claudio de; Cheng, Zhongjian; Wang, Chunlin; Truongcao, May; Lucchese, Anna Maria; Roy, Rajika; Benedict, Cindy; Goukassian, David A.; Koch, Walter J.; Kishore, Raj

doi:10.1172/jci.insight.126967

Cited by 24 publications

(48 citation statements)

References 44 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, podoplanin, a marker of lymphatic collecting vessels, is also reportedly expressed in inflammatory cells. Previous reports indicated that a high frequency of podoplanin-expressing cells appeared in the infarcted heart and facilitated local inflammation, and podoplanin neutralization improved cardiac function after myocardial infarction ( Cimini et al, 2017 ; Cimini et al, 2019 ; Quintanilla et al, 2019 ). In our study, we assessed podoplanin-expressing lymphatic vessels but not other podoplanin-expressing cells; further analysis of other podoplanin-expressing cells in our disease model would be an area for future investigation.…”

Section: Discussionmentioning

confidence: 93%

Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Song

Chen

Swanson

et al. 2020

eLife

View full text Add to dashboard Cite

The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell populations revealed that VEGFCc156s specifically modulated angiotensin II-induced inflammatory responses in cardiac and peripheral lymphatic endothelial cells. Furthermore, telemetry studies showed that while angiotensin II increased blood pressure acutely in all animals, VEGFCc156s-treated animals displayed a delayed systemic reduction in blood pressure independent of alterations in angiotensin II-mediated aortic stiffness. Overall, these results demonstrate that VEGFCc156s had a multifaceted therapeutic effect to prevent angiotensin II-induced cardiac dysfunction by improving cardiac lymphatic function, alleviating fibrosis and inflammation, and ameliorating hypertension.

show abstract

Section: Discussionmentioning

confidence: 93%

Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Song

Chen

Swanson

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…Subsequent to heat-induced antigen retrieval, heart sections were immunolabeled with primary antibodies for platelet endothelial cell adhesion molecule (PECAM-1)/cluster of differentiation 31 (CD31) (R&D AF3628) and α-smooth muscle actin (αSMA) (Sigma-Aldrich A5228) as described ( 10 ). Secondary fluorophore-conjugated antibodies (ThermoFisher A21432 , A21202 ) were then used to analyze the immunofluorescence.…”

Section: Methodsmentioning

confidence: 99%

Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging

Lieu

Traynham

Lucia

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Research on G protein-coupled receptor kinase 2 (GRK2) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic GRK2 overactivity to further investigate the consequences of long-term GRK2 on cardiac function and structure. We report for the first time that chronic GRK2 overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.

show abstract

“…Therefore, podoplanin may represent a sign of activation of a cohort of cells during different phases of postischemic myocardial wound repair and it can be involved in mechanisms of inflammation and scar formation after MI. Cimini et al (2019) investigated a neutralizing antibody treatment approach in a mouse MI model to inhibit cell-to-cell interaction of podoplanin-positive cells to inflammatory cells in the modulation of post-MI inflammation since an exacerbated and prolonged inflammatory response is the leading cause of adverse remodeling after myocardial injury (Prabhu and Frangogiannis, 2016;Frangogiannis, 2017) and reported improved cardiac function after MI with this approach. Targeted anti-inflammatory approaches were widely studied to reduce inflammation and improve cardiac repair (Frangogiannis, 2012(Frangogiannis, , 2014; although, patients treated with highly selective strategies did not show a positive outcome after therapy (Saxena et al, 2016).…”

Section: Podoplanin In the Injured Heartmentioning

confidence: 99%

“…The complete suppression of the inflammatory pathways interferes with the migration and activation of reparative and regenerative cells important for positive tissue remodeling (Saxena et al, 2016). Cimini et al (2019) demonstrated that inhibition of the interaction between podoplanin-expressing cells and podoplanin-binding cells reduce but does not fully suppress the inflammation post MI and at the same time enhance an endogenous myocardial regeneration process after ischemic injury (Cimini et al, 2019). The histological data, vis-a-vis the functional one, demonstrated that the neutralizing activity of podoplanin leads to the healthier tissue geometry organization in the treated animals compared to the scar formation in the control animals; enhanced cardiac performance, regeneration and angiogenesis post MI (Cimini et al, 2019).…”

Section: Podoplanin In the Injured Heartmentioning

confidence: 99%

Role of Podoplanin-Positive Cells in Cardiac Fibrosis and Angiogenesis After Ischemia

Cimini

Kishore

2021

Front. Physiol.

Self Cite

View full text Add to dashboard Cite

New insights into the cellular and extra-cellular composition of scar tissue after myocardial infarction (MI) have been identified. Recently, a heterogeneous podoplanin-expressing cell population has been associated with fibrogenic and inflammatory responses and lymphatic vessel growth during scar formation. Podoplanin is a mucin-like transmembrane glycoprotein that plays an important role in heart development, cell motility, tumorigenesis, and metastasis. In the adult mouse heart, podoplanin is expressed only by cardiac lymphatic endothelial cells; after MI, it is acquired with an unexpected heterogeneity by PDGFRα-, PDGFRβ-, and CD34-positive cells. Podoplanin may therefore represent a sign of activation of a cohort of progenitor cells during different phases of post-ischemic myocardial wound repair. Podoplanin binds to C-type lectin-like receptor 2 (CLEC-2) which is exclusively expressed by platelets and a variety of immune cells. CLEC-2 is upregulated in CD11bhigh cells, including monocytes and macrophages, following inflammatory stimuli. We recently published that inhibition of the interaction between podoplanin-expressing cells and podoplanin-binding cells using podoplanin-neutralizing antibodies reduces but does not fully suppress inflammation post-MI while improving heart function and scar composition after ischemic injury. These data support an emerging and alternative mechanism of interactome in the heart that, when neutralized, leads to altered inflammatory response and preservation of cardiac function and structure. The overarching objective of this review is to assimilate and discuss the available evidence on the functional role of podoplanin-positive cells on cardiac fibrosis and remodeling. A detailed characterization of cell-to-cell interactions and paracrine signals between podoplanin-expressing cells and the other type of cells that compose the heart tissue is needed to open a new line of investigation extending beyond the known function of these cells. This review attempts to discuss the role and biology of podoplanin-positive cells in the context of cardiac injury, repair, and remodeling.

show abstract

Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction

Cited by 24 publications

References 44 publications

Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging

Role of Podoplanin-Positive Cells in Cardiac Fibrosis and Angiogenesis After Ischemia

Contact Info

Product

Resources

About