Bicuspid aortic valve: phosphorylation of c-Kit and downstream targets are prognostic for future aortopathy

Grewal, Nimrat; Groot, Adriana C. Gittenberger‐de; DeRuiter, Marco C.; Klautz, Robert J.M.; Poelmann, Robert E.; Duim, Sjoerd N.; Lindeman, J.H.; Koenraadt, Wilke M C; Jongbloed, Monique R.M.; Mohamed, Salah A.; Sievers, Hans‐Hinrich; Bogers, Ad J.J.C.; Goumans, Marie–José

doi:10.1093/ejcts/ezu319

Cited by 38 publications

(52 citation statements)

References 20 publications

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“…Even though we did not measure reactive oxygen species production, we found no difference in the expression of their scavenger enzymes heme oxygenase and glutathione peroxidase. So far, all of these facts indicate a very finely tuned inflammatory process in human aortic aneurysms and therefore the recently postulated prognostic value for phosphorylation of c-kit and downstream targets in aneurysm formation fits well in this concept [20]. In this context, recent studies reported that the inhibition of cytokine IL-1 attenuates experimental development of aortic aneurysm [21], as well as activation of TGF-signalling [22].…”

Section: Discussionmentioning

confidence: 68%

Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm

Gestrich¹,

Dürr²,

Heinemann³

et al. 2014

Thorac cardiovasc Surg

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Human aortic aneurysms have been associated with inflammation and vascular remodeling. Since the endocannabinoid system modulates inflammation and tissue remodeling, we investigated its components in human aortic aneurysms. We obtained anterior aortic wall samples from patients undergoing elective surgery for aortic aneurysm or coronary artery disease as controls. Histological and molecular analysis (RT-qPCR) was performed, and endocannabinoid concentration was determined using LC-MRM. Patient characteristics were comparable between the groups except for a higher incidence of arterial hypertension and diabetes in the control group. mRNA level of cannabinoid receptors was significantly higher in aneurysms than in controls. Concentration of the endocannabinoid 2-arachidonoylglycerol was significantly higher, while the second endocannabinoid anandamide and its metabolite arachidonic acid and palmitoylethanolamide were significantly lower in aneurysms. Histology revealed persistent infiltration of newly recruited leukocytes and significantly higher mononuclear cell density in adventitia of the aneurysms. Proinflammatory environment in aneurysms was shown by significant upregulation of M-CSF and PPAR but associated with downregulation of chemokines. We found comparable collagen-stained area between the groups, significantly decreased mRNA level of CTGF, osteopontin-1, and MMP-2, and increased TIMP-4 expression in aneurysms. Our data provides evidence for endocannabinoid system activation in human aortic aneurysms, associated with persistent low-level inflammation and vascular remodeling.

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Section: Discussionmentioning

confidence: 68%

Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm

Gestrich¹,

Dürr²,

Heinemann³

et al. 2014

Thorac cardiovasc Surg

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“…The decreased TGF-β signaling could impair the expression of MYOCD and thus down regulate SMC marker gene expression, including MYH11 . Interestingly, two groups have reported separately that impaired canonical TGF-β signaling was also found in the ascending aortic tissue in BAV patients, and might potentiate the development of aneurysms in BAV (Grewal et al, 2014a, Paloschi et al, 2015). Our in vitro model provided another piece of evidence that defective TGF-β signaling might be the cause of the defective differentiation of NCSCs and the observed aortopathy in the BAV patients with ascending aortic aneurysm.…”

Section: Discussionmentioning

confidence: 99%

Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves

et al. 2016

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Individuals with bicuspid aortic valves (BAV) are at a higher risk of developing thoracic aortic aneurysms (TAA) than patients with trileaflet aortic valves (TAV). The aneurysms associated with BAV most commonly involve the ascending aorta and spare the descending aorta. Smooth muscle cells (SMCs) in the ascending and descending aorta arise from neural crest (NC) and paraxial mesoderm (PM), respectively. We hypothesized defective differentiation of the neural crest stem cells (NCSCs)-derived SMCs but not paraxial mesoderm cells (PMCs)-derived SMCs contributes to the aortopathy associated with BAV. When induced pluripotent stem cells (iPSCs) from BAV/TAA patients were differentiated into NCSC-derived SMCs, these cells demonstrated significantly decreased expression of marker of SMC differentiation (MYH11) and impaired contraction compared to normal control. In contrast, the PMC-derived SMCs were similar to control cells in these aspects. The NCSC-SMCs from the BAV/TAA also showed decreased TGF-β signaling based on phosphorylation of SMAD2, and increased mTOR signaling. Inhibition of mTOR pathway using rapamycin rescued the aberrant differentiation. Our data demonstrates that decreased differentiation and contraction of patient's NCSC-derived SMCs may contribute to that aortopathy associated with BAV.

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“…We all have been educated by the elegant and seminal work of Leonardo Da Vinci, suggesting that a semilunar valve carrying three cusps is more efficient compared to a bicuspid valve. However, in the human a bicuspid valve is the most common congenital heart “malformation,” often going undetected until later in adult life and then usually associated with aortic aneurysm . Recent investigations using transgenic mice demonstrated that mutated “OFT genes” (NOTCH, eNOS, GATA4/5, NKx2.5, and TGFβ pathway, compiled by DeWaard and Postma) are associated with bicuspidy, most likely by disturbed SHF addition and neural crest disturbances.…”

Section: Evo‐devo Aspects Of Congenital Malformationsmentioning

confidence: 99%

“…However, in the human a bicuspid valve is the most common congenital heart "malformation," often going undetected until later in adult life and then usually associated with aortic aneurysm. 143 Recent investigations using transgenic mice demonstrated that mutated "OFT genes" (NOTCH, eNOS, GATA4/5, NKx2.5, and TGFβ pathway, compiled by DeWaard and Postma 225 ) are associated with bicuspidy, most likely by disturbed SHF addition and neural crest disturbances. Considering reptiles, we know that these animals usually have bicuspid valves in their three OFT vessels and seem not to be encumbered by this situation.…”

Section: Bicuspid Semilunar Valvesmentioning

confidence: 99%

Development and evolution of the metazoan heart

Poelmann

Groot

2019

Developmental Dynamics

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The mechanisms of the evolution and development of the heart in metazoans are highlighted, starting with the evolutionary origin of the contractile cell, supposedly the precursor of cardiomyocytes. The last eukaryotic common ancestor is likely a combination of several cellular organisms containing their specific metabolic pathways and genetic signaling networks. During evolution, these tool kits diversified. Shared parts of these conserved tool kits act in the development and functioning of pumping hearts and open or closed circulations in such diverse species as arthropods, mollusks, and chordates. The genetic tool kits became more complex by gene duplications, addition of epigenetic modifications, influence of environmental factors, incorporation of viral genomes, cardiac changes necessitated by air‐breathing, and many others. We evaluate mechanisms involved in mollusks in the formation of three separate hearts and in arthropods in the formation of a tubular heart. A tubular heart is also present in embryonic stages of chordates, providing the septated four‐chambered heart, in birds and mammals passing through stages with first and second heart fields. The four‐chambered heart permits the formation of high‐pressure systemic and low‐pressure pulmonary circulation in birds and mammals, allowing for high metabolic rates and maintenance of body temperature. Crocodiles also have a (nearly) separated circulation, but their resting temperature conforms with the environment. We argue that endothermic ancestors lost the capacity to elevate their body temperature during evolution, resulting in ectothermic modern crocodilians. Finally, a clinically relevant paragraph reviews the occurrence of congenital cardiac malformations in humans as derailments of signaling pathways during embryonic development.

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Bicuspid aortic valve: phosphorylation of c-Kit and downstream targets are prognostic for future aortopathy

Abstract: Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.

Cited by 38 publications

References 20 publications

Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm

Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm

Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves

Development and evolution of the metazoan heart

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