Curt D Sigmund

University of Iowa, Iowa City, Iowa, United States

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Publications (281)1633.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (Ang II). We hypothesize that interference with endothelial PPARγ would exacerbate Ang II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of Ang II (120 ng/kg/min) or saline for 2 weeks. Ang II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in Ang II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from Ang II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from Ang II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/L), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates Ang II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against Ang II-induced endothelial dysfunction.
    Physiological Genomics 11/2015; DOI:10.1152/physiolgenomics.00087.2015 · 2.37 Impact Factor
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    ABSTRACT: Renin, the key regulated enzyme of the renin-angiotensin system regulates blood pressure, fluid-electrolyte homeostasis and renal morphogenesis. Whole body deletion of the renin gene results in severe morphological and functional derangements including thickening of renal arterioles, hydronephrosis and inability to concentrate the urine. Because renin is found in vascular and tubular cells, it has been impossible to discern the relative contribution of tubular versus vascular renin to such complex phenotype. Therefore, we deleted renin independently in the vascular and tubular compartments by crossing Ren1(c fl/fl) mice to Foxd1-cre and Hoxb7-cre mice, respectively. Deletion of renin in the vasculature resulted in neonatal mortality that could be rescued with daily injections of saline. The kidneys of surviving mice showed absence of renin, hypertrophic arteries, hydronephrosis and negligible levels of plasma renin. In contrast, lack of renin in the collecting ducts did not affect kidney morphology, intra-renal renin or circulating renin in basal conditions or in response to a homeostatic stress such as sodium depletion. We conclude that renin generated in the renal vasculature is fundamental for the development and integrity of the kidney whereas renin in the collecting ducts is dispensable for normal kidney development and cannot compensate for the lack of renin in the vascular compartment. Further, the main source of circulating renin is the kidney vasculature. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 08/2015; 309(6):ajpregu.00313.2015. DOI:10.1152/ajpregu.00313.2015 · 3.11 Impact Factor
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    ABSTRACT: Cullin-Ring ubiquitin Ligases (CRL) regulate protein turnover by promoting ubiquitination of substrate proteins, targeting them for proteasomal degradation. It was previously shown that mutations in Cullin3 (Cul3) causing deletion of 57 amino acids encoded by exon 9 (Cul3Δ9) cause hypertension. Moreover, RhoA activity contributes to vascular constriction and hypertension. We show that ubiquitination and degradation of RhoA is dependent on Cul3 in HEK293T cells in which Cul3 expression is ablated by either siRNA or by CRISPR-Cas9 genome editing. The latter was used to generate a Cul3-null cell line (HEK293T(Cul3KO)). When expressed in these cells, Cul3Δ9 supported reduced ubiquitin ligase activity toward RhoA compared to equivalent levels of wildtype Cul3 (Cul3WT). Consistent with its reduced activity, binding of Cul3Δ9 to the E3 ubiquitin ligase, Rbx1, and neddylation of Cul3Δ9 was significantly impaired compared to Cul3WT. Conversely, Cul3Δ9 bound to substrate adaptor proteins more efficiently than Cul3WT. Cul3Δ9 also forms unstable dimers with Cul3WT, thus disrupting dimers of Cul3WT complexes that are required for efficient ubiquitination of some substrates. Indeed, co-expression of Cul3WT and Cul3Δ9 in HEK293T(Cul3KO) cells resulted in a decrease in the active form of Cul3WT. We conclude that Cul3Δ9-associated ubiquitin ligase activity toward RhoA is impaired, and suggest that Cul3Δ9 mutations may act dominantly by sequestering substrate adaptors and disrupting Cul3WT complexes. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 06/2015; 290(31). DOI:10.1074/jbc.M115.645358 · 4.57 Impact Factor
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    ABSTRACT: Multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by angiotensin II (Ang II) in cultured vascular smooth muscle cells (VSMCs), but its function in experimental hypertension has not been explored. The aim of this study was to determine the impact of CaMKII inhibition selectively in VSMCs on Ang II hypertension. Transgenic expression of a CaMKII peptide inhibitor in VSMCs (TG SM-CaMKIIN model) reduced the blood pressure response to chronic Ang II infusion. The aortic depressor nerve activity was reset in hypertensive versus normotensive wild-type animals but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor activity account for the blood pressure difference between genotypes. Accordingly, aortic pulse wave velocity, a measure of arterial wall stiffness and a determinant of baroreceptor activity, increased in hypertensive versus normotensive wild-type animals but did not change in TG SM-CaMKIIN mice. Moreover, examination of blood pressure and heart rate under ganglionic blockade revealed that VSMC CaMKII inhibition abolished the augmented efferent sympathetic outflow and renal and splanchnic nerve activity in Ang II hypertension. Consequently, we hypothesized that VSMC CaMKII controls baroreceptor activity by modifying arterial wall remodeling in Ang II hypertension. Gene expression analysis in aortas from normotensive and Ang II-infused mice revealed that TG SM-CaMKIIN aortas were protected from Ang II-induced upregulation of genes that control extracellular matrix production, including collagen. VSMC CaMKII inhibition also strongly altered the expression of muscle contractile genes under Ang II. CaMKII in VSMCs regulates blood pressure under Ang II hypertension by controlling structural gene expression, wall stiffness, and baroreceptor activity. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association 06/2015; 4(6). DOI:10.1161/JAHA.115.001949 · 4.31 Impact Factor
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    ABSTRACT: Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. We tested the role of PPARγ in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). In summary, endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice. © 2015 American Heart Association, Inc.
    Hypertension 04/2015; 66(1). DOI:10.1161/HYPERTENSIONAHA.115.05332 · 6.48 Impact Factor
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    ABSTRACT: Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)-salt. Intracerebroventricular delivery of the endoplasmic reticulum stress-reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein-deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt-induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein-deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt-induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure. © 2015 American Heart Association, Inc.
    Hypertension 04/2015; 65(6). DOI:10.1161/HYPERTENSIONAHA.115.05377 · 6.48 Impact Factor
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    ABSTRACT: Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5-7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a "tissue rejection" type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein byproduct of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Further, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal and vascular systems in the non-pregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established mid-pregnancy dysfunctions that cause preeclampsia. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 03/2015; DOI:10.1152/ajpregu.00073.2015 · 3.11 Impact Factor
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    ABSTRACT: We tested the hypothesis that endothelial peroxisome proliferator-activated receptor-γ protects against vascular thrombosis using a transgenic mouse model expressing a peroxisome proliferator-activated receptor-γ mutant (E-V290M) selectively in endothelium. The time to occlusive thrombosis of the carotid artery was significantly shortened in E-V290M mice compared with nontransgenic littermates after either chemical injury with ferric chloride (5.1±0.2 versus 10.1±3.3 minutes; P=0.01) or photochemical injury with rose bengal (48±9 versus 74±9 minutes; P=0.04). Gene set enrichment analysis demonstrated the upregulation of NF-κB target genes, including P-selectin, in aortic endothelial cells from E-V290M mice (P<0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290M mice (P<0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290M mice compared with nontransgenic mice (53±8 versus 25±7 per minute; P=0.02). The shortened time to arterial occlusion in E-V290M mice was reversed by administration of P-selectin-blocking antibodies or neutrophil-depleting antibodies (P=0.04 and P=0.02, respectively) before photochemical injury. Endothelial peroxisome proliferator-activated receptor-γ protects against thrombosis through a mechanism that involves downregulation of P-selectin expression and diminished P-selectin-mediated leukocyte-endothelial interactions. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2015; 35(4). DOI:10.1161/ATVBAHA.115.305378 · 6.00 Impact Factor
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    ABSTRACT: Preeclampsia is a cardiovascular disorder of late pregnancy that is, commonly characterized by hypertension, renal structural damage and dysfunction, and fetal growth restriction. Prevailing etiologic models of this disorder include T-cell dysfunction as an initiating cause of preeclampsia. Indoleamine 2,3-dioxygenase (IDO), an enzyme that mediates the conversion of tryptophan to kynurenine, has been linked to preeclampsia in humans, and is known to regulate T-cell activity and an endothelial-derived relaxing factor. To test the hypothesis that IDO is causally involved in the pathogenesis of preeclampsia, mice deficient for IDO (IDO-KO) were generated on a C57BL/6 background. IDO-KO and wild-type C57BL/6 mice were bred, and preeclampsia phenotypes were evaluated during pregnancy. Pregnant IDO-KO mice exhibited pathognomonic renal glomerular endotheliosis, proteinuria, pregnancy-specific endothelial dysfunction, intrauterine growth restriction, and mildly elevated blood pressure compared to wild-type mice. Together these findings highlight an important role for IDO in the generation of phenotypes typical of preeclampsia. Loss of IDO function may represent a risk factor for the development of preeclampsia. By extension, increased IDO activity, reductions in IDO reactants, or increases in IDO products may represent novel therapeutic approaches for this disorder.
    01/2015; 3(1). DOI:10.14814/phy2.12257
  • Pimonrat Ketsawatsomkron · Curt D Sigmund ·
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    ABSTRACT: This review summarizes recent findings on the regulation of vascular tone by the nuclear receptor transcription factor, peroxisome proliferator activated receptor (PPAR) γ. Much of the recent work utilizes genetic tools to interrogate the significance of PPARγ in endothelial and smooth muscle cells and novel PPARγ target genes have been identified. Endothelial PPARγ prevents inflammation and oxidative stress, while promoting vasodilation by controlling the regulation of NADPH oxidase, catalase and superoxide dismutase gene expression. Moreover, the protective functions of endothelial PPARγ appear more prominent during disease conditions. Novel findings also suggest a role for endothelial PPARγ as a mediator of whole body metabolism. In smooth muscle cells, PPARγ regulates vascular tone by targeting genes involved with contraction and relaxation signaling cascades, some of which is via transcriptional activation, and some through novel mechanisms regulating protein turnover. Furthermore, aberrant changes in renin-angiotensin system components and exacerbated responses to angiotensin II induced vascular dysfunction are observed when PPARγ function is lost in smooth muscle cells. With these recent advances based partially on lessons from patients with PPARγ mutants, we conclude that vascular PPARγ is protective and plays an important role in the regulation of vascular tone.
    Current Opinion in Nephrology and Hypertension 01/2015; 24(2). DOI:10.1097/MNH.0000000000000103 · 3.86 Impact Factor
  • Jeffrey P Coble · Justin L Grobe · Alan Kim Johnson · Curt D Sigmund ·
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    ABSTRACT: It is critical for cells to maintain a homeostatic balance of water and electrolytes as disturbances can disrupt cellular function which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extra-cellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the MAP kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and Ang II. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 12/2014; 308(4):ajpregu.00486.2014. DOI:10.1152/ajpregu.00486.2014 · 3.11 Impact Factor
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    ABSTRACT: The development of the kidney arterioles is poorly understood. Mature arterioles contain several functionally and morphologically distinct cell types including smooth muscle, endothelial, and juxtaglomerular cells, and they are surrounded by interconnected pericytes, fibroblasts and other interstitial cells. We have shown that the embryonic kidney possesses all the necessary precursors for the development of the renal arterial tree, and those precursors assemble in situ to form the kidney arterioles. However the identity of those precursors was unclear. Within the embryonic kidney, several putative progenitors marked by the expression of either the winged-forkhead transcription factor 1 (Foxd1+ progenitor), the aspartyl-protease renin (Ren+ progenitor), and/or hemangioblasts (Scl+ progenitor) are likely to differentiate and endow most of the cells of the renal arterial tree. However, the lineage relationships and the role of these distinct progenitors in renal vascular morphogenesis have not been delineated. We therefore designed a series of experiments to ascertain the hierarchical lineage relationships between Foxd1+ and Ren+ progenitors and the role of these two precursors in the morphogenesis and patterning of the renal arterial tree. Results show that 1) Foxd1+ cells are the precursors for all the mural cells (renin cells, smooth muscle cells, perivascular fibroblasts and pericytes) of the renal arterial tree and glomerular mesangium and 2) Foxd1 per se directs the origin, number, orientation and cellular composition of the renal vessels. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 11/2014; 308(2):ajpregu.00428.2014. DOI:10.1152/ajpregu.00428.2014 · 3.11 Impact Factor
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    ABSTRACT: Myogenic responses by resistance vessels are a key component of autoregulation in brain, thus playing a crucial role in regulating cerebral blood flow and protecting the blood-brain barrier against potentially detrimental elevations in blood pressure. Although cerebrovascular disease is often accompanied by alterations in myogenic responses, mechanisms that control these changes are poorly understood. Peroxisome proliferator-activated receptor γ has emerged as a regulator of vascular tone. We hypothesized that interference with peroxisome proliferator-activated receptor γ in smooth muscle would augment myogenic responses in cerebral arteries. We studied transgenic mice expressing a dominant-negative mutation in peroxisome proliferator-activated receptor γ selectively in smooth muscle (S-P467L) and nontransgenic littermates. Myogenic tone in middle cerebral arteries from S-P467L was elevated 3-fold when compared with nontransgenic littermates. Rho kinase is thought to play a major role in cerebrovascular disease. The Rho kinase inhibitor, Y-27632, abolished augmented myogenic tone in middle cerebral arteries from S-P467L mice. CN-03, which modifies RhoA making it constitutively active, elevated myogenic tone to ≈60% in both strains, via a Y-27632-dependent mechanism. Large conductance Ca(2+)-activated K(+) channels (BKCa) modulate myogenic tone. Inhibitors of BKCa caused greater constriction in middle cerebral arteries from nontransgenic littermates when compared with S-P467L. Expression of RhoA or Rho kinase-I/II protein was similar in cerebral arteries from S-P467L mice. Overall, the data suggest that peroxisome proliferator-activated receptor γ in smooth muscle normally inhibits Rho kinase and promotes BKCa function, thus influencing myogenic tone in resistance arteries in brain. These findings have implications for mechanisms that underlie large- and small-vessel disease in brain, as well as regulation of cerebral blood flow.
    Hypertension 11/2014; 65(2). DOI:10.1161/HYPERTENSIONAHA.114.04541 · 6.48 Impact Factor
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  • Justin L Grobe · Curt D Sigmund ·

    Hypertension 09/2014; 64(6). DOI:10.1161/HYPERTENSIONAHA.114.04075 · 6.48 Impact Factor
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    ABSTRACT: Although peroxisome proliferator-activated receptor-γ (PPARγ) is thought to play a protective role in the vasculature, its cell-specific effect, particularly in resistance vessels, is poorly defined. Nitric oxide (NO) plays a major role in vascular biology in the brain. We examined the hypothesis that selective interference with PPARγ in vascular muscle would impair NO-dependent responses and augment vasoconstrictor responses in the cerebral circulation. We studied mice expressing a dominant negative mutation in human PPARγ (P467L) under the control of the smooth muscle myosin heavy chain promoter (S-P467L). In S-P467L mice, dilator responses to exogenously applied or endogenously produced NO were greatly impaired in cerebral arteries in vitro and in small cerebral arterioles in vivo. Select NO-independent responses, including vasodilation to low concentrations of potassium, were also impaired in S-P467L mice. In contrast, increased expression of wild-type PPARγ in smooth muscle had little effect on vasomotor responses. Mechanisms underlying impairment of both NO-dependent and NO-independent vasodilator responses after interference with PPARγ involved Rho kinase with no apparent contribution by oxidative stress-related mechanisms. These findings support the concept that via effects on Rho kinase-dependent signaling, PPARγ in vascular muscle is a major determinant of vascular tone in resistance vessels and, in particular, NO-mediated signaling in cerebral arteries and brain microvessels. Considering the importance of NO and Rho kinase, these findings have implications for regulation of cerebral blood flow and the pathogenesis of large and small vessel disease in brain.
    Hypertension 09/2014; 64(5). DOI:10.1161/HYPERTENSIONAHA.114.03935 · 6.48 Impact Factor
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    ABSTRACT: Peroxisome proliferator activated receptor γ (PPARγ) has been reported to play a protective role in the vasculature; however, the underlying mechanisms involved are not entirely known. We previously showed that vascular smooth muscle-specific overexpression of a dominant negative human PPARγ mutation in mice (S-P467L) leads to enhanced myogenic tone and increased angiotensin-II-dependent vasoconstriction. S-P467L mice also exhibit increased arterial blood pressure. Here we tested the hypotheses that a) mesenteric smooth muscle cells isolated from S-P467L mice exhibit enhanced angiotensin-II AT1 receptor signaling, and b) the increased arterial pressure of S-P467L mice is angiotensin-II AT1 receptor dependent. Phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (ERK1/2) was robustly increased in mesenteric artery smooth muscle cell cultures from S-P467L in response to angiotensin-II. The increase in ERK1/2 activation by angiotensin-II was blocked by losartan, a blocker of AT1 receptors. Angiotensin-II-induced ERK1/2 activation was also blocked by Tempol, a scavenger of reactive oxygen species, and correlated with increased Nox4 protein expression. To investigate whether endogenous renin-angiotensin system activity contributes to the elevated arterial pressure in S-P467L, non-transgenic and S-P467L mice were treated with the AT1 receptor blocker, losartan (30 mg/kg per day), for 14-days and arterial pressure was assessed by radiotelemetry. At baseline S-P467L mice showed a significant increase of systolic arterial pressure (142.0±10.2 vs 129.1±3.0 mmHg, p<0.05). Treatment with losartan lowered systolic arterial pressure in S-P467L (132.2±6.9 mmHg) to a level similar to untreated non-transgenic mice. Losartan also lowered arterial pressure in non-transgenic (113.0±3.9 mmHg) mice, such that there was no difference in the losartan-induced depressor response between groups (-13.53±1.39 in S-P467L vs -16.16±3.14 mmHg in non-transgenic). Our results suggest that interference with PPARγ in smooth muscle: a) causes enhanced angiotensin-II AT1 receptor-mediated ERK1/2 activation in resistance vessels, b) and may elevate arterial pressure through both angiotensin-II AT1 receptor-dependent and -independent mechanisms.
    PLoS ONE 08/2014; 9(8):e103786. DOI:10.1371/journal.pone.0103786 · 3.23 Impact Factor
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    ABSTRACT: The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined blood pressure and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared to controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400ng/kg/min resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 ± 4 mmHg in KO vs 128 ± 3 mmHg in controls). Urinary renin excretion and remained significantly lower in the KO mice following Ang-II infusion as compared to controls. Further, membrane associated ENaC protein levels were significantly lower in KO mice following Ang-II infusion. These findings suggest that CD renin modulates blood pressure in angiotensin II infused hypertension and these effects are associated with changes in ENaC expression.
    American journal of physiology. Renal physiology 08/2014; 307(8). DOI:10.1152/ajprenal.00367.2014 · 3.25 Impact Factor
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    ABSTRACT: Increased activity of the renin-angiotensin system within the brain elevates fluid intake, blood pressure, and resting metabolic rate. Renin and angiotensinogen are co-expressed within the same cells of the subfornical organ; and the production and action of angiotensin-II through the angiotensin-II type 1 receptor in the SFO is necessary for fluid intake due to increased activity of the brain renin-angiotensin system. We generated an inducible model of angiotensin-II production by breeding transgenic mice expressing human renin in neurons controlled by the synapsin promoter with transgenic mice containing a Cre-recombinase inducible human angiotensinogen construct. Adenoviral delivery of Cre-recombinase causes SFO-selective induction of human angiotensinogen expression. Selective production of angiotensin-II in the SFO results in increased water intake, but did not change blood pressure or resting metabolic rate. The increase in water intake was angiotensin-II type 1 receptor-dependent. When given a choice between water and 0.15M NaCl, these mice increased total fluid and sodium, but not water, because of an increased preference for NaCl. When provided a choice between water and 0.3M NaCl, the mice exhibited increased fluid, water and sodium intake, but no change in preference for NaCl. The increase in fluid intake was blocked by an inhibitor of protein kinase C, but not extracellular regulated kinases, and correlated with increased phosphorylated cyclic AMP response element binding protein in the subfornical organ. Thus increased production and action of angiotensin-II specifically in the subfornical organ is sufficient on its own to mediate an increase in drinking through protein kinase C.
    AJP Regulatory Integrative and Comparative Physiology 06/2014; 307(4). DOI:10.1152/ajpregu.00216.2014 · 3.11 Impact Factor
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    ABSTRACT: Downloaded from 1 P eroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Classically, PPARγ plays an important role in adipogenesis and metabolic processes but has recently emerged as a crucial element in cardiovascular diseases such as hypertension. Mutations of PPARγ lead to hypertension in humans and in experimental animal models.
    Hypertension 06/2014; 64. DOI:10.1161/HYPERTENSIONHA.114.03553 · 6.48 Impact Factor

Publication Stats

9k Citations
1,633.65 Total Impact Points


  • 1995-2015
    • University of Iowa
      • • Department of Internal Medicine
      • • Department of Pharmacology
      • • Department of Molecular Physiology and Biophysics
      • • Center for Functional Genomics of Hypertension
      • • Department of Anatomy and Cell Biology
      • • Department of Pathology
      Iowa City, Iowa, United States
  • 2008
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 1997-2007
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 2004
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1988-2004
    • Roswell Park Cancer Institute
      • • Department of Molecular and Cellular Biology
      • • Roswell Park Cancer Institute, Elm and Carlton Streets
      Buffalo, New York, United States
  • 1996
    • University of Sydney
      Sydney, New South Wales, Australia
  • 1982-1984
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States