Ricardo A. Peña-Silva

Dysregulation of Antioxidant Mechanisms Contributes to Increased Oxidative Stress in Calcific Aortic Valvular Stenosis in Humans

OBJECTIVES The aim of this study was to determine whether oxidative stress is increased in calcified, stenotic aortic valves and to examine mechanisms that might contribute to increased oxidative stress. BACKGROUND Oxidative stress is increased in atherosclerotic lesions and might play an important role in plaque progression and calcification. The role of oxidative stress in valve disease is not clear. METHODS Superoxide (dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence), hydrogen peroxide H2O2 (dichlorofluorescein fluorescence), and expression and activity of pro- and anti-oxidant enzymes were measured in normal valves from hearts not suitable for transplantation and stenotic aortic valves that were removed during surgical replacement of the valve. RESULTS In normal valves, superoxide levels were relatively low and distributed homogeneously throughout the valve. In stenotic valves, superoxide levels were increased 2-fold near the calcified regions of the valve (p < 0.05); noncalcified regions did not differ significantly from normal valves. Hydrogen peroxide levels were also markedly elevated in calcified regions of stenotic valves. Nicotinamide adenine dinucleotide phosphate oxidase activity was not increased in calcified regions of stenotic valves. Superoxide levels in stenotic valves were significantly reduced by inhibition of nitric oxide synthases (NOS), which suggests uncoupling of the enzyme. Antioxidant mechanisms were reduced in calcified regions of the aortic valve, because total superoxide dismutase (SOD) activity and expression of all 3 SOD isoforms was significantly decreased. Catalase expression also was reduced in pericalcific regions. CONCLUSIONS This study provides the first evidence that oxidative stress is increased in calcified regions of stenotic aortic valves from humans. Increased oxidative stress is due at least in part to reduction in expression and activity of antioxidant enzymes and perhaps to uncoupled NOS activity. Thus, mechanisms of oxidative stress differ greatly between stenotic aortic valves and atherosclerotic arteries.

Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves

Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2*.-) was measured in heart valves from explanted human hearts that were not used for transplantation. (O2*.-) levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in (O2*.-). Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased (O2*.-) levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in (O2*.-) during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated (O2*.-), and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.

Novel Role for Endogenous Hepatocyte Growth Factor in the Pathogenesis of Intracranial Aneurysms

Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) protects against vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms. Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Tissue from superficial temporal arteries and ruptured or unruptured intracranial aneurysms collected from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured human endothelial, smooth muscle cells and monocytes treated with lipopolysaccharides in presence or absence of HGF and PF-04217903. We found that HGF concentrations were significantly higher in blood collected from human intracranial aneurysms (1076±656 pg/mL) than in femoral arteries (196±436 pg/mL; P<0.001). HGF and c-Met were detected by immunostaining in superficial temporal arteries and in both ruptured and unruptured human intracranial aneurysms. A c-Met antagonist did not alter the formation of intracranial aneurysms (P>0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of vascular cell adhesion molecule-1 (P<0.05) and E-Selectin (P<0.05) in human aortic endothelial cells. In conclusion, plasma HGF concentrations are elevated in intracranial aneurysms. HGF and c-Met are expressed in superficial temporal arteries and in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelial cells and protect against intracranial aneurysm rupture.

EP1c times for angiotensin: EP1 receptors facilitate angiotensin II-induced vascular dysfunction.

A relatively recent concept is that vascular dysfunction plays a key role in cognitive impairment, as well as stroke. Impaired neurovascular coupling, probably in part through activation of the angiotensin II type 1 receptor, is central to cerebrovascular dysfunction.1 Reactive oxygen species clearly are important mediators of the deleterious vascular effects of angiotensin II. The evidence seemed to favor the concept that angiotensin II, perhaps through activation of NADPH oxidase, releases superoxide, which scavenges NO to produce cerebral vascular dysfunction.1 However, just when we thought that we understood mechanisms by which angiotensin II produces cerebrovascular dysfunction, Capone et al2 in this issue of Hypertension present compelling evidence that products of cyclooxygenase (COX) metabolism are important facilitating factors for angiotensin II signaling in cerebral blood vessels. The authors report that prostaglandin E2 (PGE2) and the type 1 PGE2 (EP1) receptor are required for endothelial dysfunction and impaired neurovascular coupling induced by acute administration of angiotensin II.2 Because the hypothesis is novel and important for our understanding of angiotensin II effects, it is desirable to have multiple lines of evidence to support the conclusion. This indeed the authors have accomplished, because they use several genetically altered mice and pharmacological inhibitors to build their case. COX-1 is involved in synthesis and release of an endothelium-derived contracting factor.3 Pressor responses to angiotensin II are attenuated in COX-1 knockout mice and …

Stages in Discovery: Angiotensin-Converting Enzyme Type 2 and Stroke.

Rapid progress in relationn to cardiovascular effects of Angiotensin 1–7 (Ang 1–7), the Mas receptor, and the angiotensin converting enzyme type 2 (ACE2) is an example of basic biomedical research which may eventually lead to an advance in care of patients. When one of us (DH) first attended the meeting of the Council for High Blood Pressure Research about 1970, the future of studies of the renin/angiotensin system (RAS) seemed limited. It looked like there was not much more to be learned, and was not a promising area of research. That judgment was comparable to the initial impression that Furchgotts endothelium derived relaxing factor was not very important1. Obviously, the renal/vascular/central RAS has proven to be important in normal cardiovascular regulation, pathophysiology, and as an enormously important therapeutic target. Another chapter of the RAS story has been written over the past two decades as the ACE2 /angiotensin 1–7/mas receptor axis has emerged. The first stage was the discovery of Ang 1–7 by Ferrario2, the role of ACE2 upon enzymatic formation of Ang 1–7 by Penninger3, and identification of the Ang 1–7 receptor, Mas, by Santos, Bader 4. The second stage was the finding that administration of exogenous ang 1–7 is sufficiently potent to produce effects on the cardiovascular system, and that the endogenous system is sufficiently potent to affect responses to several pathophysiological states5. One of the important effects of ACE2 /angiotensin 1–7/mas receptor axis is its effects on the brain and cerebral blood vessels. ACE2 and angiotensin 1–7 are important modulators of cerebrovascular function6, 7. Treatment with angiotensin 1–7 appears to protect the brain from inflammation, apoptosis and oxidative stress induced by hypertension8. Angiotensin 1–7 also appears to play an important role in cerebrovascular disease. In stroke prone hypertensive rats9 and in a mouse model of rupture of intracranial aneurysms10, angiotensin 1–7 appears to increase survival. The ACE2 /angiotensin 1–7/mas receptor axis also appears to be modulated and be beneficial in models of ischemic stroke. Levels of angiotensin 1–7, and expression of ACE2 and Mas increase after middle cerebral artery occlusion (MCAO) in rats11. Several groups have shown that intracerebroventricular (ICV) administration of angiotensin 1–7, administered before and during middle cerebral artery occlusion, may attenuate neuronal damage in rats after MCAO12–14. Similarly, indirect approaches to increase brain angiotensin 1–7 levels have been developed using ICV administration of an ACE2 activator (diaminizene), which also appears to protect the brain against ischemic damage14. Thus, several lines of evidence suggest that the ACE2 /angiotensin 1–7/mas receptor axis plays a protective role in pathophysiology of cerebrovascular disease and stroke. In the current issue of Hypertension, Bennion et al.15, extend previous studies and demonstrate that the ACE2 activator, diminazene, when given intraperitoneally, attenuates brain damage and neurological deficit after ischemic stroke. The authors used an MCAO model in which endothelin 1 is injected in the proximity of the MCA and induces vasoconstriction. Using this model, the authors report several findings. First, Brain ACE2 activity increases shortly after ischemic stroke. Second, circulating ACE2 activity is also increased 3 days after ischemic stroke. Third, inhibition of cerebral ACE2 by ICV injection of an ACE2 inhibitor (MLN-4760) did not increase infarct volume, but resulted in aggravation of neurological deficit after MCAO. Fourth, intraperitoneal injection of an ACE2 activator decreased infarct volume and neurological deficit after MCAO. Fifth, the beneficial effects of the ACE2 activator after MCAO were attenuated by ICV injection of a Mas receptor antagonist (A779). Collectively these results suggest that formation of angiotensin 1–7 and stimulation of Mas receptors is associated with the beneficial effects of ACE2 activation in ischemic stroke. The mechanisms by which ACE2 activation protects the brain after ischemic stroke are not clear, but appear to be independent of changes in blood pressure or cerebral blood flow. Protective effects of ACE2 may involve modulation of neuroinflammation, as suggested by previous studies. Importantly, although the authors used intraperitoneal injections, they demonstrated effects of the ACE2 activator in the brain. The finding is important with the potential for translation of these findings to the patient. The long term impact of interventions that target ACE2 and angiotensin 1–7 in stroke are not clear. Is the early decrease in neurological deficit associated with better prognosis and survival? Is circulating ACE2 activity a valid marker of brain damage after stroke? Would increased circulating ACE2 activity be associated with better prognosis or would it be associated with systemic inflammation and increased shedding of ACE2 by TACE? Would systemic administration of angiotensin 1–7 protect the brain after brain ischemia? The future? These studies suggest that ang 1–7/ACE2 Mas axis may protect against stroke. An ENORMOUS word of caution, however. Many studies have observed that a wide variety of interventions reduce the size of ischemic strokes in experimental models (especially in rats and mice). But these interventions have failed to reduce the size of strokes in humans. As a minimum, this area of research is clarifying mechanisms by which endogenous ang 1–7/ACE2 protect against stroke. We are far from knowing however whether ang 1–7 will be the first peptide to protect against stroke in humans.See related article, pp 141–148 Rapid progress in relation to cardiovascular effects of angiotensin 1 to 7 (Ang 1–7), the Mas receptor, and the angiotensin-converting enzyme type 2 (ACE2) is an example of basic biomedical research, which may eventually lead to an advance in care of patients. When one of us (D.H.) first attended the meeting of the Council for High Blood Pressure Research about 1970, the future of studies of the renin/angiotensin system seemed limited. It looked like there was not much more to be learned and was not a promising area of research. That judgment was comparable to the initial impression that Furchgott’s endothelium–derived relaxing factor was not important.1 Obviously, the renal/vascular/central renin/angiotensin system has proven to be important in normal cardiovascular regulation, pathophysiology, and as an enormously important therapeutic target. Figure. Brain ischemia induces neuroinflammation, apoptosis, and oxidative stress and causes brain damage. Recent studies revealed that brain ischemia may increase the circulating and local angiotensin-converting enzyme type 2 (ACE2) activity. Increased ACE2 activity may lead to increased formation of angiotensin 1 to 7 (Ang 1–7) and stimulation of Mas receptors, which may be neuroprotective. Similar effects can be obtained after local …

A Novel Role for Endogenous HGF in the Pathogenesis of Intracranial Aneurysms

Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) protects against vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms. Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Tissue from superficial temporal arteries and ruptured or unruptured intracranial aneurysms collected from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured human endothelial, smooth muscle cells and monocytes treated with lipopolysaccharides in presence or absence of HGF and PF-04217903. We found that HGF concentrations were significantly higher in blood collected from human intracranial aneurysms (1076±656 pg/mL) than in femoral arteries (196±436 pg/mL; P<0.001). HGF and c-Met were detected by immunostaining in superficial temporal arteries and in both ruptured and unruptured human intracranial aneurysms. A c-Met antagonist did not alter the formation of intracranial aneurysms (P>0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of vascular cell adhesion molecule-1 (P<0.05) and E-Selectin (P<0.05) in human aortic endothelial cells. In conclusion, plasma HGF concentrations are elevated in intracranial aneurysms. HGF and c-Met are expressed in superficial temporal arteries and in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelial cells and protect against intracranial aneurysm rupture.

Stages in Discovery

Rapid progress in relationn to cardiovascular effects of Angiotensin 1–7 (Ang 1–7), the Mas receptor, and the angiotensin converting enzyme type 2 (ACE2) is an example of basic biomedical research which may eventually lead to an advance in care of patients. When one of us (DH) first attended the meeting of the Council for High Blood Pressure Research about 1970, the future of studies of the renin/angiotensin system (RAS) seemed limited. It looked like there was not much more to be learned, and was not a promising area of research. That judgment was comparable to the initial impression that Furchgotts endothelium derived relaxing factor was not very important1. Obviously, the renal/vascular/central RAS has proven to be important in normal cardiovascular regulation, pathophysiology, and as an enormously important therapeutic target. Another chapter of the RAS story has been written over the past two decades as the ACE2 /angiotensin 1–7/mas receptor axis has emerged. The first stage was the discovery of Ang 1–7 by Ferrario2, the role of ACE2 upon enzymatic formation of Ang 1–7 by Penninger3, and identification of the Ang 1–7 receptor, Mas, by Santos, Bader 4. The second stage was the finding that administration of exogenous ang 1–7 is sufficiently potent to produce effects on the cardiovascular system, and that the endogenous system is sufficiently potent to affect responses to several pathophysiological states5. One of the important effects of ACE2 /angiotensin 1–7/mas receptor axis is its effects on the brain and cerebral blood vessels. ACE2 and angiotensin 1–7 are important modulators of cerebrovascular function6, 7. Treatment with angiotensin 1–7 appears to protect the brain from inflammation, apoptosis and oxidative stress induced by hypertension8. Angiotensin 1–7 also appears to play an important role in cerebrovascular disease. In stroke prone hypertensive rats9 and in a mouse model of rupture of intracranial aneurysms10, angiotensin 1–7 appears to increase survival. The ACE2 /angiotensin 1–7/mas receptor axis also appears to be modulated and be beneficial in models of ischemic stroke. Levels of angiotensin 1–7, and expression of ACE2 and Mas increase after middle cerebral artery occlusion (MCAO) in rats11. Several groups have shown that intracerebroventricular (ICV) administration of angiotensin 1–7, administered before and during middle cerebral artery occlusion, may attenuate neuronal damage in rats after MCAO12–14. Similarly, indirect approaches to increase brain angiotensin 1–7 levels have been developed using ICV administration of an ACE2 activator (diaminizene), which also appears to protect the brain against ischemic damage14. Thus, several lines of evidence suggest that the ACE2 /angiotensin 1–7/mas receptor axis plays a protective role in pathophysiology of cerebrovascular disease and stroke. In the current issue of Hypertension, Bennion et al.15, extend previous studies and demonstrate that the ACE2 activator, diminazene, when given intraperitoneally, attenuates brain damage and neurological deficit after ischemic stroke. The authors used an MCAO model in which endothelin 1 is injected in the proximity of the MCA and induces vasoconstriction. Using this model, the authors report several findings. First, Brain ACE2 activity increases shortly after ischemic stroke. Second, circulating ACE2 activity is also increased 3 days after ischemic stroke. Third, inhibition of cerebral ACE2 by ICV injection of an ACE2 inhibitor (MLN-4760) did not increase infarct volume, but resulted in aggravation of neurological deficit after MCAO. Fourth, intraperitoneal injection of an ACE2 activator decreased infarct volume and neurological deficit after MCAO. Fifth, the beneficial effects of the ACE2 activator after MCAO were attenuated by ICV injection of a Mas receptor antagonist (A779). Collectively these results suggest that formation of angiotensin 1–7 and stimulation of Mas receptors is associated with the beneficial effects of ACE2 activation in ischemic stroke. The mechanisms by which ACE2 activation protects the brain after ischemic stroke are not clear, but appear to be independent of changes in blood pressure or cerebral blood flow. Protective effects of ACE2 may involve modulation of neuroinflammation, as suggested by previous studies. Importantly, although the authors used intraperitoneal injections, they demonstrated effects of the ACE2 activator in the brain. The finding is important with the potential for translation of these findings to the patient. The long term impact of interventions that target ACE2 and angiotensin 1–7 in stroke are not clear. Is the early decrease in neurological deficit associated with better prognosis and survival? Is circulating ACE2 activity a valid marker of brain damage after stroke? Would increased circulating ACE2 activity be associated with better prognosis or would it be associated with systemic inflammation and increased shedding of ACE2 by TACE? Would systemic administration of angiotensin 1–7 protect the brain after brain ischemia? The future? These studies suggest that ang 1–7/ACE2 Mas axis may protect against stroke. An ENORMOUS word of caution, however. Many studies have observed that a wide variety of interventions reduce the size of ischemic strokes in experimental models (especially in rats and mice). But these interventions have failed to reduce the size of strokes in humans. As a minimum, this area of research is clarifying mechanisms by which endogenous ang 1–7/ACE2 protect against stroke. We are far from knowing however whether ang 1–7 will be the first peptide to protect against stroke in humans.See related article, pp 141–148 Rapid progress in relation to cardiovascular effects of angiotensin 1 to 7 (Ang 1–7), the Mas receptor, and the angiotensin-converting enzyme type 2 (ACE2) is an example of basic biomedical research, which may eventually lead to an advance in care of patients. When one of us (D.H.) first attended the meeting of the Council for High Blood Pressure Research about 1970, the future of studies of the renin/angiotensin system seemed limited. It looked like there was not much more to be learned and was not a promising area of research. That judgment was comparable to the initial impression that Furchgott’s endothelium–derived relaxing factor was not important.1 Obviously, the renal/vascular/central renin/angiotensin system has proven to be important in normal cardiovascular regulation, pathophysiology, and as an enormously important therapeutic target. Figure. Brain ischemia induces neuroinflammation, apoptosis, and oxidative stress and causes brain damage. Recent studies revealed that brain ischemia may increase the circulating and local angiotensin-converting enzyme type 2 (ACE2) activity. Increased ACE2 activity may lead to increased formation of angiotensin 1 to 7 (Ang 1–7) and stimulation of Mas receptors, which may be neuroprotective. Similar effects can be obtained after local …

Stages in Discovery: ACE2 and Stroke

Rapid progress in relationn to cardiovascular effects of Angiotensin 1–7 (Ang 1–7), the Mas receptor, and the angiotensin converting enzyme type 2 (ACE2) is an example of basic biomedical research which may eventually lead to an advance in care of patients. When one of us (DH) first attended the meeting of the Council for High Blood Pressure Research about 1970, the future of studies of the renin/angiotensin system (RAS) seemed limited. It looked like there was not much more to be learned, and was not a promising area of research. That judgment was comparable to the initial impression that Furchgotts endothelium derived relaxing factor was not very important1. Obviously, the renal/vascular/central RAS has proven to be important in normal cardiovascular regulation, pathophysiology, and as an enormously important therapeutic target. Another chapter of the RAS story has been written over the past two decades as the ACE2 /angiotensin 1–7/mas receptor axis has emerged. The first stage was the discovery of Ang 1–7 by Ferrario2, the role of ACE2 upon enzymatic formation of Ang 1–7 by Penninger3, and identification of the Ang 1–7 receptor, Mas, by Santos, Bader 4. The second stage was the finding that administration of exogenous ang 1–7 is sufficiently potent to produce effects on the cardiovascular system, and that the endogenous system is sufficiently potent to affect responses to several pathophysiological states5. One of the important effects of ACE2 /angiotensin 1–7/mas receptor axis is its effects on the brain and cerebral blood vessels. ACE2 and angiotensin 1–7 are important modulators of cerebrovascular function6, 7. Treatment with angiotensin 1–7 appears to protect the brain from inflammation, apoptosis and oxidative stress induced by hypertension8. Angiotensin 1–7 also appears to play an important role in cerebrovascular disease. In stroke prone hypertensive rats9 and in a mouse model of rupture of intracranial aneurysms10, angiotensin 1–7 appears to increase survival. The ACE2 /angiotensin 1–7/mas receptor axis also appears to be modulated and be beneficial in models of ischemic stroke. Levels of angiotensin 1–7, and expression of ACE2 and Mas increase after middle cerebral artery occlusion (MCAO) in rats11. Several groups have shown that intracerebroventricular (ICV) administration of angiotensin 1–7, administered before and during middle cerebral artery occlusion, may attenuate neuronal damage in rats after MCAO12–14. Similarly, indirect approaches to increase brain angiotensin 1–7 levels have been developed using ICV administration of an ACE2 activator (diaminizene), which also appears to protect the brain against ischemic damage14. Thus, several lines of evidence suggest that the ACE2 /angiotensin 1–7/mas receptor axis plays a protective role in pathophysiology of cerebrovascular disease and stroke. In the current issue of Hypertension, Bennion et al.15, extend previous studies and demonstrate that the ACE2 activator, diminazene, when given intraperitoneally, attenuates brain damage and neurological deficit after ischemic stroke. The authors used an MCAO model in which endothelin 1 is injected in the proximity of the MCA and induces vasoconstriction. Using this model, the authors report several findings. First, Brain ACE2 activity increases shortly after ischemic stroke. Second, circulating ACE2 activity is also increased 3 days after ischemic stroke. Third, inhibition of cerebral ACE2 by ICV injection of an ACE2 inhibitor (MLN-4760) did not increase infarct volume, but resulted in aggravation of neurological deficit after MCAO. Fourth, intraperitoneal injection of an ACE2 activator decreased infarct volume and neurological deficit after MCAO. Fifth, the beneficial effects of the ACE2 activator after MCAO were attenuated by ICV injection of a Mas receptor antagonist (A779). Collectively these results suggest that formation of angiotensin 1–7 and stimulation of Mas receptors is associated with the beneficial effects of ACE2 activation in ischemic stroke. The mechanisms by which ACE2 activation protects the brain after ischemic stroke are not clear, but appear to be independent of changes in blood pressure or cerebral blood flow. Protective effects of ACE2 may involve modulation of neuroinflammation, as suggested by previous studies. Importantly, although the authors used intraperitoneal injections, they demonstrated effects of the ACE2 activator in the brain. The finding is important with the potential for translation of these findings to the patient. The long term impact of interventions that target ACE2 and angiotensin 1–7 in stroke are not clear. Is the early decrease in neurological deficit associated with better prognosis and survival? Is circulating ACE2 activity a valid marker of brain damage after stroke? Would increased circulating ACE2 activity be associated with better prognosis or would it be associated with systemic inflammation and increased shedding of ACE2 by TACE? Would systemic administration of angiotensin 1–7 protect the brain after brain ischemia? The future? These studies suggest that ang 1–7/ACE2 Mas axis may protect against stroke. An ENORMOUS word of caution, however. Many studies have observed that a wide variety of interventions reduce the size of ischemic strokes in experimental models (especially in rats and mice). But these interventions have failed to reduce the size of strokes in humans. As a minimum, this area of research is clarifying mechanisms by which endogenous ang 1–7/ACE2 protect against stroke. We are far from knowing however whether ang 1–7 will be the first peptide to protect against stroke in humans.See related article, pp 141–148 Rapid progress in relation to cardiovascular effects of angiotensin 1 to 7 (Ang 1–7), the Mas receptor, and the angiotensin-converting enzyme type 2 (ACE2) is an example of basic biomedical research, which may eventually lead to an advance in care of patients. When one of us (D.H.) first attended the meeting of the Council for High Blood Pressure Research about 1970, the future of studies of the renin/angiotensin system seemed limited. It looked like there was not much more to be learned and was not a promising area of research. That judgment was comparable to the initial impression that Furchgott’s endothelium–derived relaxing factor was not important.1 Obviously, the renal/vascular/central renin/angiotensin system has proven to be important in normal cardiovascular regulation, pathophysiology, and as an enormously important therapeutic target. Figure. Brain ischemia induces neuroinflammation, apoptosis, and oxidative stress and causes brain damage. Recent studies revealed that brain ischemia may increase the circulating and local angiotensin-converting enzyme type 2 (ACE2) activity. Increased ACE2 activity may lead to increased formation of angiotensin 1 to 7 (Ang 1–7) and stimulation of Mas receptors, which may be neuroprotective. Similar effects can be obtained after local …

Novel Role for Endogenous Hepatocyte Growth Factor in the Pathogenesis of Intracranial AneurysmsNovelty and Significance

Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) protects against vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms. Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Tissue from superficial temporal arteries and ruptured or unruptured intracranial aneurysms collected from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured human endothelial, smooth muscle cells and monocytes treated with lipopolysaccharides in presence or absence of HGF and PF-04217903. We found that HGF concentrations were significantly higher in blood collected from human intracranial aneurysms (1076±656 pg/mL) than in femoral arteries (196±436 pg/mL; P<0.001). HGF and c-Met were detected by immunostaining in superficial temporal arteries and in both ruptured and unruptured human intracranial aneurysms. A c-Met antagonist did not alter the formation of intracranial aneurysms (P>0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of vascular cell adhesion molecule-1 (P<0.05) and E-Selectin (P<0.05) in human aortic endothelial cells. In conclusion, plasma HGF concentrations are elevated in intracranial aneurysms. HGF and c-Met are expressed in superficial temporal arteries and in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelial cells and protect against intracranial aneurysm rupture.

Response to Letter Regarding Article, “Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging”

We appreciate the interest of Dr Tsuda in our study.1 In our article we showed that angiotensin-converting enzyme type 2 (ACE2) deficiency is associated with impaired endothelial function in cerebral arteries from adult mice and augmented endothelial dysfunction during aging. In those experiments, we used acetylcholine to gain insight into endothelial function because acetylcholine is also a neurotransmitter known to be …