Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure

Kapur, Navin K.; Wilson, Susan F.; Yunis, Adil; Qiao, Xiaoying; Mackey, Emily; Paruchuri, Vikram; Baker, Corey; Aronovitz, Mark; Karumanchi, S. Ananth; Letarte, Michelle; Kass, David A.; Mendelsohn, Michael E.; Karas, Richard H.

doi:10.1161/circulationaha.111.080002

Cited by 105 publications

(103 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mechanistically, sEng may works through interrupting transforming growth factor-β1 signaling, a pathway that has been previously linked with cardiac fibrosis. 35 Whether sEng is synergistic with sFlt1 in its effects on myocardial function or whether this is an adaptive response is unknown. Placental growth factor levels (a proangiogenic protein) in this cohort did not correlate with cardiac dysfunction (data not shown), suggesting that the driver of the cardiac dysfunction in preeclampsia is likely mediated by antiangiogenic factors.…”

Section: Discussionmentioning

confidence: 99%

Circulating Antiangiogenic Factors and Myocardial Dysfunction in Hypertensive Disorders of Pregnancy

et al. 2016

Self Cite

View full text Add to dashboard Cite

H ypertensive disorders of pregnancy (HDP) affect 5% to 10% of pregnant women, 1 are the most common medical complication of pregnancy in developed countries, 2 and are a leading cause of maternal and fetal death worldwide. 3 HDP include preeclampsia, gestational hypertension, chronic hypertension, and superimposed preeclampsia. Preeclampsia targets the vascular endothelium causing widespread maternal vascular endothelial dysfunction. Antiangiogenic proteins have been implicated as being pathogenic in the development of the observed vascular endothelial dysfunction. 4Overexpression of soluble fms-like tyrosine kinase-1 (sFlt1), an endogenous vascular endothelial growth factor inhibitor, is associated with preeclampsia-like phenotypes in a rodent model and symptoms diminish with the addition of vascular endothelial growth factor or placental growth factor. [5][6][7] Multiple human clinical studies have established that levels of the sFlt1 and soluble endoglin (sEng) increase in the circulation of pregnant women with preeclampsia. 4,6,[8][9][10] sFlt1 and sEng levels are elevated weeks before the clinical onset of preeclampsia, and the degree of elevation correlates with adverse maternal and fetal outcomes. 8,[11][12][13][14][15][16] Few adverse outcomes occur in the absence of angiogenic factor abnormalities. 17,18 Although previous studies have detected changes in myocardial function in HDP, 19,20 a direct association between preeclampsia biomarkers, including sFlt1 and sEng, has not been described. In other abnormal cardiovascular states such as congestive heart failure, increased circulating levels of antiangiogenic proteins have been associated with development of endothelial vascular dysfunction, myocardial dysfunction, and adverse cardiovascular outcomes. 21Women with HDP have abnormalities in both systolic and diastolic cardiac function that seem before clinical symptoms.19,22 Despite preservation of left ventricular ejection fraction (LVEF), 23 longitudinal muscle fiber shortening is decreased, suggesting the presence of subclinical left ventricular systolic dysfunction. 20 This finding suggests a Abstract-Hypertensive disorders of pregnancy (HDP) are associated with subclinical changes in cardiac function. Although the mechanism underlying this finding is unknown, elevated levels of soluble antiangiogenic proteins such as soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng) are associated with myocardial dysfunction and may play a role. We hypothesized that these antiangiogenic proteins may contribute to the development of cardiac dysfunction in HDP. We prospectively studied 207 pregnant women with HDP and nonhypertensive controls and evaluated whether changes in global longitudinal strain (GLS) observed on echocardiography is specific for HDP and whether these changes correlate with HDP biomarkers, sFlt1 and sEng. A total of 62 (30%) patients were diagnosed with preeclampsia (group A), 105 (51%) did not have an HDP (group B), and 40 (19%) were diagnosed with chronic or gestational hype...

show abstract

Section: Discussionmentioning

confidence: 99%

Circulating Antiangiogenic Factors and Myocardial Dysfunction in Hypertensive Disorders of Pregnancy

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…In agreement with these reports, our present data in the UUO model of tubulo-interstitial fibrosis shows the increase in both Eng mRNA and protein expression in the O kidney ( Figure 1). Several authors demonstrated that Eng promotes fibrosis in different kidney experimental models [15,16,[33][34][35][36][37] and other experimental models of tissue fibrosis in organs such as heart [13,38], liver [39] or skin [40]. Two different Eng isoforms that differs exclusively in the intracellular tail have been reported in both humans [18] and mice [19].…”

Section: Discussionmentioning

confidence: 99%

“…Eng is a TGF-β1 co-receptor that participates in TGF-β1 signaling, and many studies have addressed the involvement of Eng in several fibrotic processes [11][12][13][14][15][16]. Eng is overexpressed in kidneys of patients with chronic kidney disease [17] and in kidneys of animals with several experimental models of renal fibrosis [15].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

Muñoz‐Félix

Pérez-Roque

Núñez-Gómez

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Transforming growth factor beta 1 (TGF-β1) is one of the most studied cytokines involved in renal tubulo-interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-β1 actions in different biological processes, including ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG(+)) and we have performed an UUO in S-ENG(+) and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG(+) mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG(+) mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain.

show abstract

“…118). Using human samples, these authors described that endoglin expression is elevated in human failing hearts and that the major source for plasma endoglin was the cardiac fibroblasts.…”

Section: Increased Levels Of Endoglin In Fibrotic Diseasesmentioning

confidence: 99%

The role of endoglin in kidney fibrosis

Muñoz‐Félix

Oujo

López‐Novoa

2014

Expert Rev. Mol. Med.

View full text Add to dashboard Cite

Tubulointerstitial fibrosis and glomerulosclerosis, are a major feature of end stage chronic kidney disease (CKD), characterised by an excessive accumulation of extracellular matrix (ECM) proteins. Transforming growth factor beta-1 (TGF-β1) is a cytokine with an important role in many steps of renal fibrosis such as myofibroblast activation and proliferation, ECM protein synthesis and inflammatory cell infiltration. Endoglin is a TGF-β co-receptor that modulates TGF-β responses in different cell types. In numerous cells types, such as mesangial cells or myoblasts, endoglin regulates negatively TGF-β-induced ECM protein expression. However, recently it has been demonstrated that 'in vivo' endoglin promotes fibrotic responses. Furthermore, several studies have demonstrated an increase of endoglin expression in experimental models of renal fibrosis in the kidney and other tissues. Nevertheless, the role of endoglin in renal fibrosis development is unclear and a question arises: Does endoglin protect against renal fibrosis or promotes its development? The purpose of this review is to critically analyse the recent knowledge relating to endoglin and renal fibrosis. Knowledge of endoglin role in this pathology is necessary to consider endoglin as a possible therapeutic target against renal fibrosis.

show abstract

Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure

Cited by 105 publications

References 43 publications

Circulating Antiangiogenic Factors and Myocardial Dysfunction in Hypertensive Disorders of Pregnancy

Circulating Antiangiogenic Factors and Myocardial Dysfunction in Hypertensive Disorders of Pregnancy

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

The role of endoglin in kidney fibrosis

Contact Info

Product

Resources

About