Doctoral thesis, UCL (University College London)., Aug 28, 2016
Bcl-2 B-cell lymphoma 2 BK Ca Large conductance calcium activated potassium channel BMPR2 Bone mo... more Bcl-2 B-cell lymphoma 2 BK Ca Large conductance calcium activated potassium channel BMPR2 Bone morphogenetic protein receptor type 2 BNP Brain natriuretic peptide BREATHE Bosentan Randomised trial of Endothelin Antagonist Therapy Ca 2+ Calcium cAMP Cyclic adenosine monophosphate
Aims: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. ... more Aims: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are shown to be elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. Methods & Results: Circulating total annexin v+ (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) originwere quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls.The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p=1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. Conclusions: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of ongoing inflammation, endothelial injury and may explain ongoing prothrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy.
Prostaglandins & Other Lipid Mediators, Jul 1, 2015
Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in wh... more Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI 2 (EP 3), iloprost (EP 1), treprostinil (EP 2 , DP 1) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which prostacyclin and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells, and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined, whether selectively for the IP receptor gives rise to superior or inferior clinical benefit in PAH.
International Journal of Molecular Sciences, Aug 31, 2020
Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in w... more Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.
Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammat... more Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammation is thought to be a key player in PAH and stimulates the release of submicron vesicles known as microparticles (MPs) from various cells including endothelial cells. These MPs have shown to be elevated in pulmonary hypertension and correlate with disease severity. A hallmark of PAH is medial thickening but it is unclear whether MPs might be released from vascular smooth muscle cells into the circulation from PAH patients after endothelial damage. Aim: We investigated whether MPs could be detected and characterised after an inflammatory insult on pulmonary arterial smooth muscle cells (PASMCs) isolated from PAH patients. Methods: Serum with or without the mitogen PDGF-BB was used to stimulate PASMCs and Platelet derived growth factor receptor β (PDGFRβ), endoglin, ICAM1, MCAM, VCAM1, KDR, α smooth muscle actin, sm22α, and annexin V MPs were measured by flow cytometry. Results: Levels of annexin V+ total MPs were significantly increased after PDGF-BB stimulation after 24 hours compared to serum control (p
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Background Colorectal cancer (CRC) is the second cause of cancer death worldwide. Screening for C... more Background Colorectal cancer (CRC) is the second cause of cancer death worldwide. Screening for CRC by Faecal Immunochemical Test (FIT) aims to detect early cases before symptoms occur. Yet, the FIT has poor predictive value and low compliance rate. To address this, the role of circulating microvesicles as potential screening tool is a novel approach that warrants prioritised research. Methods In a two-gate diagnostic accuracy study, 35 patients with benign colorectal polyps (BCRP) (n=16) and colorectal cancer (CRC) (n=19) were compared to 17 age-matched healthy controls. Total annexin-V positive microvesicles and sub-populations positive for selected biomarkers relevant to bowel neoplasm were evaluated in patients’ plasma using flow cytometry. Results Total plasma microvesicles, and sub-populations positive for CD31, CD42a, CD31+/CD42a-, EPHB2, ICAM and LGR5 (component factor-1) were able to identify patients with BCRP and CRC with a receiver operator curve (AUC) accuracy of a 100%...
Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in w... more Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in...
Objectives We aim to investigate whether circulating microparticle (CMPs) subsets were raised amo... more Objectives We aim to investigate whether circulating microparticle (CMPs) subsets were raised amongst people living with HIV in Malawi, and whether they associated with arterial stiffness. Methods ART-naive adults with a new HIV diagnosis and CD4 <100 cells/uL had microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic BP and diastolic BP in a 1:1 ratio. Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. Results The median (IQ) total CMP count was 12 fold higher in participants with HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.42, p<0.001). In adjusted analysis, every log increase in circulating particles showed a 20% increase in cfPWV (95% CI 4 to 40%, p=0.02). In terms of subsets, endothelial and platelet derived microparti...
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, Jan 13, 2016
Previous studies of an association between physical activity and inflammatory bowel disease have ... more Previous studies of an association between physical activity and inflammatory bowel disease have yielded conflicting results. This meta-analysis was conducted to clarify whether there is an association between physical activity and inflammatory bowel disease. The PubMed and Web of Science databases were searched for relevant studies published up to October 2015. Data were extracted and the summary relative risks (RRs) were calculated using a random effects or a fixed-effects model, according to heterogeneity. Seven studies were included in the analysis. Relative to individuals with low physical activity, those who participated in high physical activity had an RR of 0.63 (95% CI, 0.50-0.79) for developing Crohn's disease. In stratified analyses, a significantly lower risk for Crohn's disease was associated with high physical activity in Europeans only (RR, 0.62; 95% CI, 0.43-0.91); population-based control studies (RR, 0.56; 95% CI, 0.41-0.76); and case-control studies (RR, 0...
Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammat... more Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammation is thought to be a key player in PAH and stimulates the release of submicron vesicles known as microparticles (MPs) from various cells including endothelial cells. These MPs have shown to be elevated in pulmonary hypertension and correlate with disease severity. A hallmark of PAH is medial thickening but it is unclear whether MPs might be released from vascular smooth muscle cells into the circulation from PAH patients after endothelial damage. Aim: We investigated whether MPs could be detected and characterised after an inflammatory insult on pulmonary arterial smooth muscle cells (PASMCs) isolated from PAH patients. Methods: Serum with or without the mitogen PDGF-BB was used to stimulate PASMCs and Platelet derived growth factor receptor β (PDGFRβ), endoglin, ICAM1, MCAM, VCAM1, KDR, α smooth muscle actin, sm22α, and annexin V MPs were measured by flow cytometry. Results: Levels of annexin V+ total MPs were significantly increased after PDGF-BB stimulation after 24 hours compared to serum control (p
Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in wh... more Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin (PGI2) therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI2 (EP3), iloprost (EP1), treprostinil (EP2, DP1) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which PGI2 and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined whether selectivity for the IP receptor gives rise to a superior or inferior clinical benefit in PAH.
Background: We aimed to investigate whether circulating microparticle (CMPs) subsets were raised ... more Background: We aimed to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with human immunodeficiency virus (HIV) and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. Methods: Antiretroviral therapy (ART)-naïve adults with a new HIV diagnosis and CD4 <100 cells/µL had microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic blood pressure (BP) and diastolic BP in a 1:1 ratio. Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. Results: The median (IQ) total CMP count for 71 participants was 1 log higher in HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.47, p<0.001). In adjusted analysis, every log increase in circulating particles showed ...
Doctoral thesis, UCL (University College London)., Aug 28, 2016
Bcl-2 B-cell lymphoma 2 BK Ca Large conductance calcium activated potassium channel BMPR2 Bone mo... more Bcl-2 B-cell lymphoma 2 BK Ca Large conductance calcium activated potassium channel BMPR2 Bone morphogenetic protein receptor type 2 BNP Brain natriuretic peptide BREATHE Bosentan Randomised trial of Endothelin Antagonist Therapy Ca 2+ Calcium cAMP Cyclic adenosine monophosphate
Aims: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. ... more Aims: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are shown to be elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. Methods & Results: Circulating total annexin v+ (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) originwere quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls.The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p=1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. Conclusions: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of ongoing inflammation, endothelial injury and may explain ongoing prothrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy.
Prostaglandins & Other Lipid Mediators, Jul 1, 2015
Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in wh... more Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI 2 (EP 3), iloprost (EP 1), treprostinil (EP 2 , DP 1) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which prostacyclin and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells, and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined, whether selectively for the IP receptor gives rise to superior or inferior clinical benefit in PAH.
International Journal of Molecular Sciences, Aug 31, 2020
Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in w... more Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.
Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammat... more Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammation is thought to be a key player in PAH and stimulates the release of submicron vesicles known as microparticles (MPs) from various cells including endothelial cells. These MPs have shown to be elevated in pulmonary hypertension and correlate with disease severity. A hallmark of PAH is medial thickening but it is unclear whether MPs might be released from vascular smooth muscle cells into the circulation from PAH patients after endothelial damage. Aim: We investigated whether MPs could be detected and characterised after an inflammatory insult on pulmonary arterial smooth muscle cells (PASMCs) isolated from PAH patients. Methods: Serum with or without the mitogen PDGF-BB was used to stimulate PASMCs and Platelet derived growth factor receptor β (PDGFRβ), endoglin, ICAM1, MCAM, VCAM1, KDR, α smooth muscle actin, sm22α, and annexin V MPs were measured by flow cytometry. Results: Levels of annexin V+ total MPs were significantly increased after PDGF-BB stimulation after 24 hours compared to serum control (p
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Background Colorectal cancer (CRC) is the second cause of cancer death worldwide. Screening for C... more Background Colorectal cancer (CRC) is the second cause of cancer death worldwide. Screening for CRC by Faecal Immunochemical Test (FIT) aims to detect early cases before symptoms occur. Yet, the FIT has poor predictive value and low compliance rate. To address this, the role of circulating microvesicles as potential screening tool is a novel approach that warrants prioritised research. Methods In a two-gate diagnostic accuracy study, 35 patients with benign colorectal polyps (BCRP) (n=16) and colorectal cancer (CRC) (n=19) were compared to 17 age-matched healthy controls. Total annexin-V positive microvesicles and sub-populations positive for selected biomarkers relevant to bowel neoplasm were evaluated in patients’ plasma using flow cytometry. Results Total plasma microvesicles, and sub-populations positive for CD31, CD42a, CD31+/CD42a-, EPHB2, ICAM and LGR5 (component factor-1) were able to identify patients with BCRP and CRC with a receiver operator curve (AUC) accuracy of a 100%...
Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in w... more Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in...
Objectives We aim to investigate whether circulating microparticle (CMPs) subsets were raised amo... more Objectives We aim to investigate whether circulating microparticle (CMPs) subsets were raised amongst people living with HIV in Malawi, and whether they associated with arterial stiffness. Methods ART-naive adults with a new HIV diagnosis and CD4 <100 cells/uL had microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic BP and diastolic BP in a 1:1 ratio. Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. Results The median (IQ) total CMP count was 12 fold higher in participants with HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.42, p<0.001). In adjusted analysis, every log increase in circulating particles showed a 20% increase in cfPWV (95% CI 4 to 40%, p=0.02). In terms of subsets, endothelial and platelet derived microparti...
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, Jan 13, 2016
Previous studies of an association between physical activity and inflammatory bowel disease have ... more Previous studies of an association between physical activity and inflammatory bowel disease have yielded conflicting results. This meta-analysis was conducted to clarify whether there is an association between physical activity and inflammatory bowel disease. The PubMed and Web of Science databases were searched for relevant studies published up to October 2015. Data were extracted and the summary relative risks (RRs) were calculated using a random effects or a fixed-effects model, according to heterogeneity. Seven studies were included in the analysis. Relative to individuals with low physical activity, those who participated in high physical activity had an RR of 0.63 (95% CI, 0.50-0.79) for developing Crohn's disease. In stratified analyses, a significantly lower risk for Crohn's disease was associated with high physical activity in Europeans only (RR, 0.62; 95% CI, 0.43-0.91); population-based control studies (RR, 0.56; 95% CI, 0.41-0.76); and case-control studies (RR, 0...
Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammat... more Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammation is thought to be a key player in PAH and stimulates the release of submicron vesicles known as microparticles (MPs) from various cells including endothelial cells. These MPs have shown to be elevated in pulmonary hypertension and correlate with disease severity. A hallmark of PAH is medial thickening but it is unclear whether MPs might be released from vascular smooth muscle cells into the circulation from PAH patients after endothelial damage. Aim: We investigated whether MPs could be detected and characterised after an inflammatory insult on pulmonary arterial smooth muscle cells (PASMCs) isolated from PAH patients. Methods: Serum with or without the mitogen PDGF-BB was used to stimulate PASMCs and Platelet derived growth factor receptor β (PDGFRβ), endoglin, ICAM1, MCAM, VCAM1, KDR, α smooth muscle actin, sm22α, and annexin V MPs were measured by flow cytometry. Results: Levels of annexin V+ total MPs were significantly increased after PDGF-BB stimulation after 24 hours compared to serum control (p
Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in wh... more Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin (PGI2) therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI2 (EP3), iloprost (EP1), treprostinil (EP2, DP1) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which PGI2 and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined whether selectivity for the IP receptor gives rise to a superior or inferior clinical benefit in PAH.
Background: We aimed to investigate whether circulating microparticle (CMPs) subsets were raised ... more Background: We aimed to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with human immunodeficiency virus (HIV) and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. Methods: Antiretroviral therapy (ART)-naïve adults with a new HIV diagnosis and CD4 <100 cells/µL had microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic blood pressure (BP) and diastolic BP in a 1:1 ratio. Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. Results: The median (IQ) total CMP count for 71 participants was 1 log higher in HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.47, p<0.001). In adjusted analysis, every log increase in circulating particles showed ...
Uploads
Papers by Rijan Gurung