Center for Vascular Biology

Brookline, MA, United States

Center for Vascular Biology

Brookline, MA, United States
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News Article | May 25, 2017
Site: www.sciencedaily.com

Blood platelets shore up open wounds and help cuts heal, but they can also cause heart attacks and strokes when a congealed ball of platelets known as a thrombus breaks free from a site of injury and gets lodged in blood vessels that feed oxygen to the brain or heart. Blood thinners, such as aspirin, reduce the risk of thrombus formation but also interfere with the initial clot formation that is essential for preventing blood loss from the wounds. Now researchers have discovered that a molecule plays a role in thrombus development, but not the initial clot formation, suggesting a new avenue for developing more specific and protective blood thinners. The results were published May 24 in the journal PLOS ONE. "The Holy Grail of our field is to reduce unwanted thrombus formation without completely blocking other important platelet functions," says senior author Ulhas Naik, Ph.D., Director of the Center for Vascular Biology at Thomas Jefferson University's Cardeza Foundation for Hematologic Research. After platelets become activated at the site of an injury, they become linked to one another forming a platelet plug. The platelets then continue to change shape, trap red blood cells and the clot begins to tighten and pull together, which can help bring two sides of a wound in closer. But this process of clot retraction is also responsible for creating the free-floating ball of a thrombus capable of blocking vital blood flow. Clot retraction is governed by a signaling process called outside-in signaling. In earlier work Dr. Naik and colleagues showed that the protein called CIB1 was involved in thrombus formation. Mice that lacked the CIB1 gene were less likely to form a thrombus. That work also suggested that mice lacking the CIB1 were still able to form a platelet plug, suggesting that this gene was involved only in the process of thrombus formation. To investigate this possibility further, and to demonstrate that the process was relevant to human physiology, the current study used human platelets, and probed the molecules that interacted with CIB1 at different time points after platelet activation. The researchers showed that CIB1 does not begin to bind and interact with platelet molecular machinery until after platelets send out sticky protrusions that allow them to cross-link to one another and begin to form a plug. The paper, to which Dr. Naik's entire nuclear family contributed, also elucidated a number of molecules that CIB1 interacts with during outside-in signaling and thrombus formation. A clearer picture of this process could in turn be useful for researchers studying other diseases that involve platelets, such as cancer, specifically the role platelets play in metastasis or helping seed cancer in distant parts of the body. "This work demonstrates that CIB1 could be a good anti-thrombotic drug target," says Dr. Naik. "If we block CIB1, it hampers thrombus formation without interfering with platelet plug formation. If developed further, blocking CIB1 could reduce the risk of heart attack and stroke without increasing the risk for excessive bleeding that is the trade-off of current medication." The next steps for Dr. Naik and collaborating researchers include screening for small-molecule compounds that would inhibit CIB1 and which could be developed into new therapies.


News Article | May 24, 2017
Site: www.eurekalert.org

PHILADELPHIA -- Blood platelets shore up open wounds and help cuts heal, but they can also cause heart attacks and strokes when a congealed ball of platelets known as a thrombus breaks free from a site of injury and gets lodged in blood vessels that feed oxygen to the brain or heart. Blood thinners, such as aspirin, reduce the risk of thrombus formation but also interfere with the initial clot formation that is essential for preventing blood loss from the wounds. Now researchers have discovered that a molecule plays a role in thrombus development, but not the initial clot formation, suggesting a new avenue for developing more specific and protective blood thinners. The results were published May 24 in the journal PLOS ONE. "The Holy Grail of our field is to reduce unwanted thrombus formation without completely blocking other important platelet functions," says senior author Ulhas Naik, Ph.D., Director of the Center for Vascular Biology at Thomas Jefferson University's Cardeza Foundation for Hematologic Research. After platelets become activated at the site of an injury, they become linked to one another forming a platelet plug. The platelets then continue to change shape, trap red blood cells and the clot begins to tighten and pull together, which can help bring two sides of a wound in closer. But this process of clot retraction is also responsible for creating the free-floating ball of a thrombus capable of blocking vital blood flow. Clot retraction is governed by a signaling process called outside-in signaling. In earlier work Dr. Naik and colleagues showed that the protein called CIB1 was involved in thrombus formation. Mice that lacked the CIB1 gene were less likely to form a thrombus. That work also suggested that mice lacking the CIB1 were still able to form a platelet plug, suggesting that this gene was involved only in the process of thrombus formation. To investigate this possibility further, and to demonstrate that the process was relevant to human physiology, the current study used human platelets, and probed the molecules that interacted with CIB1 at different time points after platelet activation. The researchers showed that CIB1 does not begin to bind and interact with platelet molecular machinery until after platelets send out sticky protrusions that allow them to cross-link to one another and begin to form a plug. The paper, to which Dr. Naik's entire nuclear family contributed, also elucidated a number of molecules that CIB1 interacts with during outside-in signaling and thrombus formation. A clearer picture of this process could in turn be useful for researchers studying other diseases that involve platelets, such as cancer, specifically the role platelets play in metastasis or helping seed cancer in distant parts of the body. "This work demonstrates that CIB1 could be a good anti-thrombotic drug target," says Dr. Naik. "If we block CIB1, it hampers thrombus formation without interfering with platelet plug formation. If developed further, blocking CIB1 could reduce the risk of heart attack and stroke without increasing the risk for excessive bleeding that is the trade-off of current medication." The next steps for Dr. Naik and collaborating researchers include screening for small-molecule compounds that would inhibit CIB1 and which could be developed into new therapies. Article Reference: M.U. Naik, et al., "Binding of CIB1 to the αIIb tail of αIIbβ3 is required for FAK recruitment and activation in platelets" PLOS ONE. 2017. https:/ This work was supported by the grants from the NHLBI (National Heart, Lung, Blood Institute) HL 57630 and HL113188. The authors report no conflicts of interest. Jefferson, through its academic and clinical entities of Thomas Jefferson University and Jefferson Health, including Abington Health and Aria Health, is reimagining health care for the greater Philadelphia region and southern New Jersey. Jefferson has 23,000 people dedicated to providing the highest-quality, compassionate clinical care for patients, educating the health professionals of tomorrow, and discovering new treatments and therapies to define the future of care. With a university and hospital that date back to 1824, today Jefferson is comprised of six colleges, nine hospitals, 35 outpatient and urgent care locations, and a multitude of physician practices throughout the region, serving more than 100,000 inpatients, 373,000 emergency patients and 2.2 million outpatients annually.


Harrison D.G.,Center for Vascular Biology | Harrison D.G.,Vanderbilt University | Sung H.-J.,Vanderbilt University
ACS Nano | Year: 2015

In regions of the circulation where vessels are straight and unbranched, blood flow is laminar and unidirectional. In contrast, at sites of curvature, branch points, and regions distal to stenoses, blood flow becomes disturbed. Atherosclerosis preferentially develops in these regions of disturbed blood flow. Current therapies for atherosclerosis are systemic and may not sufficiently target these atheroprone regions. In this study, we sought to leverage the alterations on the luminal surface of endothelial cells caused by this atheroprone flow for nanocarrier targeting. In vivo phage display was used to discover unique peptides that selectively bind to atheroprone regions in the mouse partial carotid artery ligation model. The peptide GSPREYTSYMPH (PREY) was found to bind 4.5-fold more avidly to the region of disturbed flow and was used to form targeted liposomes. When administered intravenously, PREY-targeted liposomes preferentially accumulated in endothelial cells in the partially occluded carotid artery and other areas of disturbed flow. Proteomic analysis and immunoblotting indicated that fibronectin and Filamin-A were preferentially bound by PREY nanocarriers in vessels with disturbed flow. In additional experiments, PREY nanocarriers were used therapeutically to deliver the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), which we have previously shown to be deficient in regions of disturbed flow. This intervention increased vascular BH4 and reduced vascular superoxide in the partially ligated artery in wild-type mice and reduced plaque burden in the partially ligated left carotid artery of fat fed atheroprone mice (ApoE-/-). Targeting atheroprone sites of the circulation with functionalized nanocarriers provides a promising approach for prevention of early atherosclerotic lesion formation. © 2015 American Chemical Society.


Secor E.R.,onn Health Center | Szczepanek S.M.,Carole and Ray Neag Comprehensive Cancer Center | Singh A.,Nestlé | Guernsey L.,onn Health Center | And 5 more authors.
Evidence-based Complementary and Alternative Medicine | Year: 2012

Bromelain (Br) is a cysteine peptidase (GenBank AEH26024.1) from pineapple, with over 40 years of clinical use. The constituents mediating its anti-inflammatory activity are not thoroughly characterized and no peptide biomarker exists. Our objective is to characterize Br raw material and identify peptides in the plasma of Br treated mice. After SDS-PAGE in-gel digestion, Br (VN#3507; Middletown, CT, USA) peptides were analyzed via LC/MS/MS using 95% protein probability, 95% peptide probability, and a minimum peptide number = 5. Br spiked mouse plasma (1 ug/ul) and plasma from i.p. treated mice (12 mg/kg) were assessed using SRM. In Br raw material, we identified seven proteins: four proteases, one jacalin-like lectin, and two protease inhibitors. In Br spiked mouse plasma, six proteins (ananain, bromelain inhibitor, cysteine proteinase AN11, FB1035 precursor, FBSB precursor, and jacalin-like lectin) were identified. Using LC/MS/MS, we identified the unique peptide, DYGAVNEVK, derived from FB1035, in the plasma of i.p. Br treated mice. The spectral count of this peptide peaked at 6 hrs and was undetectable by 24 hrs. In this study, a novel Br peptide was identified in the plasma of treated mice for the first time. This Br peptide could serve as a biomarker to standardize the therapeutic dose and maximize clinical utility. © 2012 Eric R. Secor Jr. et al.


Li M.-H.,Center for Vascular Biology | Swenson R.,Arroyo Biosciences LLC | Harel M.,Connecticut Children’s Medical Center | Jana S.,TCG Life science Ltd | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2015

The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P1-5) play critical roles in many pathologic processes, including cancer. The S1P axis has become a bona fide therapeutic target in cancer. JTE-013 [N-(2,6-dichloro-4- pyridinyl)-2-[1,3-dimethyl-4-(1-methylethyl)-1H-pyrazolo[3,4-b] pyridin-6-yl]-hydrazinecarboxamide], a known S1P2 antagonist, suffers from instability in vivo. Structurally modified, more potent, and stable S1P2 inhibitors would be desirable pharmacological tools. One of the JTE-013 derivatives, AB1 [N-(1H-4-isopropyl- 1-allyl-3-methylpyrazolo[3,4-b]pyridine-6-yl)-amino-N9-(2,6- dichloropyridine-4-yl) urea], exhibited improved S1P2 antagonism compared with JTE-013. Intravenous pharmacokinetics indicated enhanced stability or slower clearance of AB1 in vivo. Migration assays in glioblastoma showed that AB1 was slightly more effective than JTE-013 in blocking S1P2-mediated inhibition of cell migration. Functional studies in the neuroblastoma (NB) cell line SK-N-AS showed that AB1 displayed potency at least equivalent to JTE-013 in affecting signaling molecules downstream of S1P2. Similarly, AB1 inhibition of the growth of SK-N-AS tumor xenografts was improved compared with JTE-013. Cell viability assays excluded that this enhanced AB1 effect is caused by inhibition of cancer cell survival. Both JTE-013 and AB1 trended to inhibit (C-C motif) ligand 2 expression and were able to significantly inhibit subsequent tumor-associated macrophage infiltration in NB xenografts. Interestingly, AB1 was more effective than JTE-013 in inhibiting the expression of the profibrotic mediator connective tissue growth factor. The terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling assay and cleaved caspase-3 detection further demonstrated that apoptosis was increased in AB1-treated NB xenografts compared with JTE-013. Overall, the modification of JTE-013 to produce the AB1 compound improved potency, intravenous pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clinical and experimental applicability. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Lu Z.,Minneapolis | Lu Z.,Center for Vascular Biology | Xu X.,Minneapolis | Xu X.,Center for Vascular Biology | And 19 more authors.
Circulation | Year: 2010

Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. METHODS AND RESULTS: Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased ≥4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3′-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. CONCLUSIONS: Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF. © 2010 American Heart Association, Inc.


Karumanchi S.A.,Harvard University | Karumanchi S.A.,Center for Vascular Biology
Hypertension | Year: 2016

During the past decade, epidemiological, experimental, and therapeutic studies have provided evidence that altered antiangiogenic state because of altered circulating sFlt1 and related proteins, such as PlGF and sEng leads to preeclampsia.109 Recent study suggests that sFlt1 and sEng are largely expressed in syncytial knots in the placenta and released into maternal circulation as syncytial microparticles.42 Understanding the dysregulated antiangiogenic pathway in the syncytium and its role in mediating maternal vascular disease marks a significant advance in our efforts to explain the origins of preeclampsia. Further study on the basic biology of placentation and syncytialization may shed clues on fundamental molecular defect in preeclampsia. Several clinical studies have demonstrated a potential role for the use of angiogenic biomarkers for aid in the diagnosis and prognosis of preterm preeclampsia. We now need clinical trials demonstrating the use of these biomarkers in helping obstetrician's management decisions, improve health outcomes or reduce costs to the healthcare system. Targeted therapies against angiogenic pathway are promising; however, only time will prove whether they will be effective. After decades of modest progress, in the past few years, the field has witnessed remarkable successes with the use of biomarkers and the development of therapies targeting specific molecular pathways and have brought hope to numerous women worldwide. In addition, we speculate that exposure to antiangiogenic factors during preeclampsia may lead to longterm changes to the vasculature that can have adverse consequences to maternal health. © 2016 American Heart Association, Inc.

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