sFRP4 signalling of apoptosis and angiostasis uses nitric oxide-cGMP-permeability axis of endothelium

Saran, Uttara; Mani, Krishna Priya; Balaguru, Uma Maheswari; Swaminathan, Akila; Nagarajan, Sankari; Dharmarajan, Arun; Chatterjee, Suvro

doi:10.1016/j.niox.2017.02.012

Cited by 16 publications

(8 citation statements)

References 52 publications

(73 reference statements)

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“…HUVEC treated with the sGC inhibitor ODQ showed an increase in apoptosis in EC exposed to DF that was also observed in both HAEC and HUVEC treated with iCRT5, a specific inhibitor of β-catenin transcriptional activity. Our findings are supported by Saran et al 31 who showed that the pro-apoptotic antagonist of Wnt signalling, sFRP4, causes endothelial dysfunction by suppressing NO-cGMP signalling.…”

Section: Discussionsupporting

confidence: 90%

β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

et al. 2020

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Increased endothelial cell (EC) apoptosis is associated with the development of atherosclerotic plaques that develop predominantly at sites exposed to disturbed flow (DF). Strategies to promote EC survival may therefore represent a novel therapeutic approach in cardiovascular disease. Nitric oxide (NO) and β-catenin have both been shown to promote cell survival and they interact in ECs as we previously demonstrated. Here we investigated the physiological role of β-catenin as a mediator of NO-induced cell survival in ECs. We found that β-catenin depleted human umbilical vein ECs (HUVEC) stimulated with pharmacological activators of endothelial NO synthase (eNOS) showed a reduction in eNOS phosphorylation (Ser1177) as well as reduced intracellular cyclic guanosine monophosphate levels compared to control cells in static cultures. In addition, β-catenin depletion abrogated the protective effects of the NO donor, Snitroso-N-acetylpenicillamine, during TNFα-and H 2 O 2-induced apoptosis. Using an orbital shaker to generate shear stress, we confirmed eNOS and β-catenin interaction in HUVEC exposed to undisturbed flow and DF and showed that β-catenin depletion reduced eNOS phosphorylation. β-catenin depletion promoted apoptosis exclusively in HUVEC exposed to DF as did inhibition of soluble guanylate cyclase (sGC) or β-catenin transcriptional activity. The expression of the pro-survival genes, Bcl-2 and survivin was also reduced following inhibition of β-catenin transcriptional activity, as was the expression of eNOS. In conclusion, our data demonstrate that β-catenin is a positive regulator of eNOS activity and cell survival in human ECs. sGC activity and β-catenin-dependent transcription of Bcl-2, survivin, BIRC3 and eNOS are essential to maintain cell survival in ECs under DF.

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Section: Discussionsupporting

confidence: 90%

β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

et al. 2020

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“…This data is consistent with other reports showing that the NO system response acts as an anti-inflammatory agent through inhibition of apoptosis on cells. 36 BPC 157 Promotes Angiogenesis Through NO Response Following Clopidogrel-Induced Gastric Ulcer…”

Section: Bpc 157 Attenuates Clopidogrel-induced Gastric Mucosa Cells mentioning

confidence: 99%

<p>Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157</p>

Wu¹,

Wei²,

Li³

et al. 2020

DDDT

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Aim Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. Methods We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A ( VEGF-A ) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP , angiogenic markers VEGF-A and its receptor VEGFR1 , and endothelial NO synthase ( eNOS ) were all analyzed by Western blot. Results This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS . Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B ( AKT ) and p38 mitogen-activated protein kinase ( p38/MAPK ). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. Conclusion In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated- AKT/p38/MAPK signaling pathways.

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“…In addition, diverse blood cells also contribute to NO availability in the vicinity to endothelium. Dr. Suvro Chatterjee's group at Anna University, Chennai has been investigating NO-cGMP signaling in endothelial permeability, nonalcoholic fatty liver disease (NAFLD), atherosclerosis and during mechanical stresses in RBCs(Balaguru et al, 2016, Nagarajan et al, 2016, Saran et al, 2017, Seth et al, 2017 and are summarizedhere. Rho GTPases downstream effecter, Rho-associated protein kinase (ROCK) isapotential target for cardiovascular diseases.Interestingly, ROCK inhibitorY-27631 was found to modulate NO production in endothelial cells in a biphasic manner suggesting caution for its use in cardiovascular diseases (Kolluru et al, 2014) and advocated a combination therapy of chemotherapeutic drugs and cGMP analogs, which would confer better protection against chemotherapy mediated vascular dysfunctions in cancer patients (Gajalakshmi et al, 2013).…”

Section: Studies On Cardiovascular System and Related Pathological Comentioning

confidence: 99%

“…Secreted Frizzled-Related Protein 4 (sFRP4), a secreted glycoprotein caused endothelial dysfunction followed by suppression of angiogenesis. Saran et al dissected the mechanism of sFRP4 mediated inhibition of angiogenesis that envisaged NO-cGMP signaling and elevated corresponding ROS levels and apoptosis for the induction of endothelial dysfunctions (Saran et al, 2017).…”

Section: Studies On Cardiovascular System and Related Pathological Comentioning

confidence: 99%

Recent Advancement in Nitric Oxide Research in India

Gaikwad¹,

Kumar²,

Dikshit³

2018

Proceedings of the Indian National Science Academy

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Discovery of nitric oxide (NO), as endothelial derived relaxing factor that has been awarded with Nobel Prize, highlights its importance as master signalling molecule in diverse systems. Recent research has unfolded several unknown facets of this intriguing biomolecule in cardiovascular system, immunomodulation neurotransmission and plant physiology. NO produced by nitric oxide synthases (NOSs), is a short lived radical that reacts with superoxide radicals to generate reactive nitrogen species and potent oxidant, peroxynitrite implying damage in various pathological conditions. This adds another level of complexity in the understanding of pathological conditions associated with NO paucity or due to increased reactive oxygen nitrogen species (RONS). Researchers from India have been instrumental in unfolding various important and novel functions of this molecule and associated signalling by using multipronged approaches in different systems. Association of NO signaling with increased burden of life style diseases in recent years provide sufficient rationale to investigate NO in diverse pathophysiological conditions in Indian perspective. Here we review recent and important contributions of Indian science during last five years in understanding of NO signaling fundamentals in human, animals and also plants, its association with diverse pathological conditions and therapeutic targeting with possible ameliorative strategies.

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sFRP4 signalling of apoptosis and angiostasis uses nitric oxide-cGMP-permeability axis of endothelium

Cited by 16 publications

References 52 publications

β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

<p>Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157</p>

Recent Advancement in Nitric Oxide Research in India

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