The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction

Abdelrahim Alqudah, Ross McNally, Naomi Todd, David Grieve, Tracy Robson, Lana McClements

Research output: Contribution to conferenceAbstract

Abstract

People with diabetes have a five-fold higher incidence of cardiovascular disease, the leading cause of death globally. FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis. A first-in-class clinical FKBPL peptide mimetic, ALM201, has successfully completed clinical trials for treatment of solid tumours. FKBPL haploinsufficient (Fkbpl± ) mice, have a pro-angiogenic phenotype, accompanied by vascular dysfunction. Vascular dysfunction is associated with CVD and T2D.In view of these findings, we now investigate a specific role for FKBPL in angiogenesis associated with cardiac dysfunction. In streptozotocin (STZ)-induced diabetic mice (50 mg/kg i.p. for 5 consecutive days), cardiac FKBPL mRNA levels were downregulated at 12 weeks compared to vehicle controls (p<0.05, n=5); this was associated with diastolic dysfunction (e.g. mitral valve E/A ratio). Similarly, in an experimental mouse model of myocardial infarction (MI) associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were downregulated versus sham controls (n≥3). Complementary in vitro studies using human umbilical vein endothelial cells (HUVEC) demonstrated increased migration and differentiation following 24 hour exposure to hypoxia (1%) when compared to normoxia (p<0.01, n=6). In addition, FKBPL protein levels were downregulated following exposure to hypoxia (p<0.01, n=6), whilst activation of HIF-1α in normoxia by 24 hour DMOG treatment led to a two-fold reduction in FKBPL protein levels (p<0.01, n=3). Furthermore, HUVEC exposed to high glucose (30 mM for 24 hour) demonstrated downregulation of FKBPL compared to osmotic control (p<0.05, n=3). Interestingly, fenofibrate (50 µM) treatment was able to restore HUVEC levels of FKBPL in hypoxia (p<0.01, n=3). In conclusion, FKBPL may serve a key regulatory role in pathological angiogenesis associated with cardiac dysfunction and, as such, could be promising as a novel biomarker and therapeutic target in this disease setting.
Original languageEnglish
Publication statusPublished - 03 Feb 2018
EventScottish Cardiovascular Forum - Trinity College Dublin
Duration: 03 Feb 201803 Feb 2018

Conference

ConferenceScottish Cardiovascular Forum
Period03/02/201803/02/2018

Fingerprint

Angiogenic Proteins
Human Umbilical Vein Endothelial Cells
Down-Regulation
Pathologic Neovascularization
Blood Vessels
Proteins
Physiologic Neovascularization
Fenofibrate
Messenger RNA
Streptozocin
Mitral Valve
Cause of Death
Theoretical Models
Cardiovascular Diseases
Ischemia
Biomarkers
Myocardial Infarction
Clinical Trials
Phenotype
Glucose

Cite this

Alqudah, A., McNally, R., Todd, N., Grieve, D., Robson, T., & McClements, L. (2018).  The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction. Abstract from Scottish Cardiovascular Forum, .
Alqudah, Abdelrahim ; McNally, Ross ; Todd, Naomi ; Grieve, David ; Robson, Tracy ; McClements, Lana. /  The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction. Abstract from Scottish Cardiovascular Forum, .
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abstract = "People with diabetes have a five-fold higher incidence of cardiovascular disease, the leading cause of death globally. FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis. A first-in-class clinical FKBPL peptide mimetic, ALM201, has successfully completed clinical trials for treatment of solid tumours. FKBPL haploinsufficient (Fkbpl± ) mice, have a pro-angiogenic phenotype, accompanied by vascular dysfunction. Vascular dysfunction is associated with CVD and T2D.In view of these findings, we now investigate a specific role for FKBPL in angiogenesis associated with cardiac dysfunction. In streptozotocin (STZ)-induced diabetic mice (50 mg/kg i.p. for 5 consecutive days), cardiac FKBPL mRNA levels were downregulated at 12 weeks compared to vehicle controls (p<0.05, n=5); this was associated with diastolic dysfunction (e.g. mitral valve E/A ratio). Similarly, in an experimental mouse model of myocardial infarction (MI) associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were downregulated versus sham controls (n≥3). Complementary in vitro studies using human umbilical vein endothelial cells (HUVEC) demonstrated increased migration and differentiation following 24 hour exposure to hypoxia (1{\%}) when compared to normoxia (p<0.01, n=6). In addition, FKBPL protein levels were downregulated following exposure to hypoxia (p<0.01, n=6), whilst activation of HIF-1α in normoxia by 24 hour DMOG treatment led to a two-fold reduction in FKBPL protein levels (p<0.01, n=3). Furthermore, HUVEC exposed to high glucose (30 mM for 24 hour) demonstrated downregulation of FKBPL compared to osmotic control (p<0.05, n=3). Interestingly, fenofibrate (50 µM) treatment was able to restore HUVEC levels of FKBPL in hypoxia (p<0.01, n=3). In conclusion, FKBPL may serve a key regulatory role in pathological angiogenesis associated with cardiac dysfunction and, as such, could be promising as a novel biomarker and therapeutic target in this disease setting.",
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Alqudah, A, McNally, R, Todd, N, Grieve, D, Robson, T & McClements, L 2018, ' The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction', Scottish Cardiovascular Forum, 03/02/2018 - 03/02/2018.

 The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction. / Alqudah, Abdelrahim; McNally, Ross; Todd, Naomi; Grieve, David; Robson, Tracy; McClements, Lana.

2018. Abstract from Scottish Cardiovascular Forum, .

Research output: Contribution to conferenceAbstract

TY - CONF

T1 -  The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction

AU - Alqudah, Abdelrahim

AU - McNally, Ross

AU - Todd, Naomi

AU - Grieve, David

AU - Robson, Tracy

AU - McClements, Lana

PY - 2018/2/3

Y1 - 2018/2/3

N2 - People with diabetes have a five-fold higher incidence of cardiovascular disease, the leading cause of death globally. FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis. A first-in-class clinical FKBPL peptide mimetic, ALM201, has successfully completed clinical trials for treatment of solid tumours. FKBPL haploinsufficient (Fkbpl± ) mice, have a pro-angiogenic phenotype, accompanied by vascular dysfunction. Vascular dysfunction is associated with CVD and T2D.In view of these findings, we now investigate a specific role for FKBPL in angiogenesis associated with cardiac dysfunction. In streptozotocin (STZ)-induced diabetic mice (50 mg/kg i.p. for 5 consecutive days), cardiac FKBPL mRNA levels were downregulated at 12 weeks compared to vehicle controls (p<0.05, n=5); this was associated with diastolic dysfunction (e.g. mitral valve E/A ratio). Similarly, in an experimental mouse model of myocardial infarction (MI) associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were downregulated versus sham controls (n≥3). Complementary in vitro studies using human umbilical vein endothelial cells (HUVEC) demonstrated increased migration and differentiation following 24 hour exposure to hypoxia (1%) when compared to normoxia (p<0.01, n=6). In addition, FKBPL protein levels were downregulated following exposure to hypoxia (p<0.01, n=6), whilst activation of HIF-1α in normoxia by 24 hour DMOG treatment led to a two-fold reduction in FKBPL protein levels (p<0.01, n=3). Furthermore, HUVEC exposed to high glucose (30 mM for 24 hour) demonstrated downregulation of FKBPL compared to osmotic control (p<0.05, n=3). Interestingly, fenofibrate (50 µM) treatment was able to restore HUVEC levels of FKBPL in hypoxia (p<0.01, n=3). In conclusion, FKBPL may serve a key regulatory role in pathological angiogenesis associated with cardiac dysfunction and, as such, could be promising as a novel biomarker and therapeutic target in this disease setting.

AB - People with diabetes have a five-fold higher incidence of cardiovascular disease, the leading cause of death globally. FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis. A first-in-class clinical FKBPL peptide mimetic, ALM201, has successfully completed clinical trials for treatment of solid tumours. FKBPL haploinsufficient (Fkbpl± ) mice, have a pro-angiogenic phenotype, accompanied by vascular dysfunction. Vascular dysfunction is associated with CVD and T2D.In view of these findings, we now investigate a specific role for FKBPL in angiogenesis associated with cardiac dysfunction. In streptozotocin (STZ)-induced diabetic mice (50 mg/kg i.p. for 5 consecutive days), cardiac FKBPL mRNA levels were downregulated at 12 weeks compared to vehicle controls (p<0.05, n=5); this was associated with diastolic dysfunction (e.g. mitral valve E/A ratio). Similarly, in an experimental mouse model of myocardial infarction (MI) associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were downregulated versus sham controls (n≥3). Complementary in vitro studies using human umbilical vein endothelial cells (HUVEC) demonstrated increased migration and differentiation following 24 hour exposure to hypoxia (1%) when compared to normoxia (p<0.01, n=6). In addition, FKBPL protein levels were downregulated following exposure to hypoxia (p<0.01, n=6), whilst activation of HIF-1α in normoxia by 24 hour DMOG treatment led to a two-fold reduction in FKBPL protein levels (p<0.01, n=3). Furthermore, HUVEC exposed to high glucose (30 mM for 24 hour) demonstrated downregulation of FKBPL compared to osmotic control (p<0.05, n=3). Interestingly, fenofibrate (50 µM) treatment was able to restore HUVEC levels of FKBPL in hypoxia (p<0.01, n=3). In conclusion, FKBPL may serve a key regulatory role in pathological angiogenesis associated with cardiac dysfunction and, as such, could be promising as a novel biomarker and therapeutic target in this disease setting.

M3 - Abstract

ER -

Alqudah A, McNally R, Todd N, Grieve D, Robson T, McClements L.  The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction. 2018. Abstract from Scottish Cardiovascular Forum, .