Aab Cardiovascular Research Institute
Aab Cardiovascular Research Institute
Xue C.,Aab Cardiovascular Research Institute |
Xue C.,University of Rochester |
Sowden M.,University of Rochester |
Berk B.C.,Aab Cardiovascular Research Institute |
Berk B.C.,University of Rochester
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2017
Objective-Oxidative stress and inflammation play key roles in the development of pulmonary arterial hypertension (PAH). Cyclophilin A (CypA) is secreted in response to oxidative stress and promotes inflammation and cardiovascular disease. Endothelial cell (EC) dysfunction is an early event in the pathogenesis of PAH. We evaluated the role of extracellular CypA in PAH and compared the effects of acetylated CypA (AcK-CypA, increased by oxidative stress) and CypA on EC dysfunction. Approach and Results-In transgenic mice that express high levels of CypA in EC specifically, a PAH phenotype was observed at 3 months including increased right ventricular systolic pressure, α-smooth muscle actin expression in small arterioles, and CD45-positive cells in the lungs. Mechanistic analysis using cultured mouse pulmonary microvascular EC and human pulmonary microvascular EC showed that extracellular CypA and AcK-CypA stimulated EC inflammatory signals: increased VCAM1 (vascular cell adhesion molecule 1) and ICAM1 (intercellular adhesion molecule 1), phosphorylation of p65, and degradation of IkB. Extracellular CypA and AcK-CypA increased EC apoptosis measured by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining, Apo-ONE assay, and caspase 3 cleavage. Oxidative stress stimulated CypA and AcK-CypA secretion, which further promoted EC oxidative stress. AcK-CypA, compared with CypA, stimulated greater increases in apoptosis, inflammation, and oxidative stress. MM284, a specific inhibitor of extracellular CypA, attenuated EC apoptosis induced by CypA and AcK-CypA. Conclusions-EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation, and oxidative stress. Our results suggest that inhibiting secreted extracellular CypA is a novel therapeutic approach for PAH. © 2017 American Heart Association, Inc.
Auerbach D.S.,Aab Cardiovascular Research Institute |
Gross R.A.,University of Rochester |
Dirksen R.T.,University of Rochester
Neurology | Year: 2016
Objectives: The coprevalence, severity, and biomarkers for seizures and arrhythmias in long QT syndrome (LQTS) remain incompletely understood. Methods: Using the Rochester-based LQTS Registry, this study included large cohorts of LQTS1-3 participants (LQTS +, n 965) and those without a LQTS mutation (LQTS -, n 936). Results: Compared to LQTS - participants, there was a higher prevalence of LQTS1, LQTS2, and LQTS + participants classified as having seizures (p < 0.001, i.e., history of seizures/epilepsy or antiseizure medication). LQTS + participants with longer corrected QT interval (QT c) durations were more likely to have seizures. LQTS2 mutations in the KCNH2 pore domain were positive predictors for both arrhythmias and seizures. In contrast, mutations in the cyclic nucleotide binding domain (cNBD) of KCNH2 conferred a negative risk of seizures, but not arrhythmias. LQTS2, KCNH2-pore, KCNH2-cNBD, QT c duration, and sex were independent predictors of seizures. LQTS + participants with seizures had significantly longer QT c durations, and a history of seizures was the strongest independent predictor of arrhythmias (hazard ratio 4.09, 95% confidence interval 2.63-6.36, p < 0.001). Conclusions: This study highlights potential biomarkers for neurocardiac electrical abnormalities in LQTS. © 2016 American Academy of Neurology.
Casey L.M.,Aab Cardiovascular Research Institute |
Pistner A.R.,Aab Cardiovascular Research Institute |
Belmonte S.L.,Aab Cardiovascular Research Institute |
Migdalovich D.,Aab Cardiovascular Research Institute |
And 9 more authors.
Circulation Research | Year: 2010
Rationale: Excess signaling through cardiac Gβγ subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein-coupled receptor kinase (GRK)2 to agonist-stimulated β-adrenergic receptors (β-ARs) in HF, leading to chronic β-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting Gβγ signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule Gβγ inhibition in HF. Methods and Results: We recently described novel small molecule Gβγ inhibitors that selectively block Gβγ-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of Gβγ and GRK2 in vitro and in HL60 cells. Here, we show they reduced β-AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to β-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and β-myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological Gβγ signaling in the treatment of HF. © 2010 American Heart Association. All rights reserved.
Batchu S.N.,Aab Cardiovascular Research Institute |
Hughson A.,University of Rochester |
Gerloff J.,Aab Cardiovascular Research Institute |
Fowell D.J.,University of Rochester |
And 2 more authors.
Hypertension | Year: 2013
The Gas6/Axl pathway regulates many cell functions and is implicated in hypertension. In this study, we aimed to investigate the role of Axl in immune cells on initiation and progression of salt-dependent hypertension. Deoxycorticosterone acetate (75 mg/60 days release)-salt hypertension was induced for 1 week or 6 weeks in Axl chimeras generated by bone marrow transplant to restrict Axl deficiency to hematopoietic or nonhematopoietic compartments. Depletion of Axl in hematopoietic cells (Axl-/- →Axl+/+) reduced (133±2 mm Hg) increase in systolic blood pressure compared with other Axl chimeras (≈150 mm Hg) 1 week after deoxycorticosterone acetate-salt. Urine protein and renal oxidative stress were lowest in Axl-/- →Axl+/+ at 1 week after deoxycorticosterone acetate-salt. Compensatory increase in Gas6 in kidneys of recipient Axl-/- may affect kidney function and blood pressure in early phase of hypertension. Flow cytometry on kidneys from Axl-/- →Axl+/+ showed increase in total leukocytes, B, and dendritic cells and decrease in macrophages compared with Axl+/+ →Axl +/+. These immune changes were associated with decrease in proinflammatory gene expression, in particular interferon γ. Systolic blood pressure returned to baseline in Axl-/- →Axl+/+ and Axl-/- →Axl-/- but remained increased in Axl+/+ →Axl+/+ and Axl+/+ →Axl -/- chimeras after 6 weeks of deoxycorticosterone acetate-salt. Vascular apoptosis was increased in the global Axl-/- chimeras in the late phase of hypertension. In summary, we found that expression of Axl in hematopoietic cells is critical for kidney pathology in early phase of salt-dependent hypertension. However, Axl in both hematopoietic and nonhematopoietic lineages contributes to the late phase of hypertension. © 2013 American Heart Association, Inc.
Pang J.,Aab Cardiovascular Research Institute |
Xu X.,University of Rochester |
Getman M.R.,Aab Cardiovascular Research Institute |
Shi X.,Aab Cardiovascular Research Institute |
And 5 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2011
G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multi-function scaffold protein. However, little is known about its physiological role in the heart. Here we sought to identify the cardiac function of GIT1. Global GIT1 knockout (KO) mice were generated and exhibited significant cardiac hypertrophy that progressed to heart failure. Electron microscopy revealed that the hearts of GIT1 KO mice demonstrated significant morphological abnormities in mitochondria, including decreased mitochondrial volume density, cristae density and increased vacuoles. Moreover, mitochondrial biogenesis-related gene peroxisome proliferator-activated receptor γ (PPARγ) co-activator-1α (PGC-1α), PGC-1β, mitochondrial transcription factor A (Tfam) expression, and total mitochondrial DNA were remarkably decreased in hearts of GIT1 KO mice. These animals also had impaired mitochondrial function, as evidenced by reduced ATP production and dissipated mitochondrial membrane potential (Ψ m) in adult cardiomyocytes. Concordant with these mitochondrial observations, GIT1 KO mice showed enhanced cardiomyocyte apoptosis and cardiac dysfunction. In conclusion, our findings identify GIT1 as a new regulator of mitochondrial biogenesis and function, which is necessary for postnatal cardiac maturation. © 2011 Elsevier Ltd.
Morrell C.N.,Aab Cardiovascular Research Institute |
Maggirwar S.B.,University of Rochester
Current Opinion in Hematology | Year: 2011
Purpose of Review: The story of platelet activation is complex, involving many intertwined and overlapping pathways and processes that continue to expand in complexity. This review will cover some of the recent novel mediators and receptors identified to be important in platelet activation. Recent Findings: Many newly discovered platelet activators and receptors are not strong platelet agonists, but rather are important modifiers of platelet activation, and thus represent potentially novel targets to blunt, but not totally prevent, platelet activation and thrombus formation. The diversity of platelet activation mediators and receptors also expands as we learn more about the disease processes that are either initiated or accelerated by platelets. Although platelets are a unique cell type with a unique role in thrombosis, they share a surprising amount in common with the molecules and machinery present in synaptic termini and immune cells. Many of these secreted molecules have important roles in platelet activation. Summary: Many newly identified platelet activators are weak agonists. These represent intriguing targets for platelet inhibitor development or shed light on the overlap between inflammation and thrombosis. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Zhao J.,Aab Cardiovascular Research Institute |
Wang W.,Aab Cardiovascular Research Institute |
Ha C.H.,Aab Cardiovascular Research Institute |
Kim J.Y.,Aab Cardiovascular Research Institute |
And 7 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011
Objective- Grb2-associated binder 1 (Gab1), a scaffolding adaptor protein, plays an important role in transmitting key signals that control cell growth, differentiation, and function from multiple tyrosine kinase receptors. The study was designed to investigate the role of endothelial Gab1 in angiogenesis and its underlying molecular mechanisms. Methods and Results- Using Cre-Lox recombination technology, we generated endothelial-specific Gab1 knockout (Gab1-ecKO) mice. Gab1-ecKO mice are viable and showed no obvious developmental defects in the vascular system. To analyze the role of Gab1 in postnatal angiogenesis, we used hindlimb ischemia and Matrigel plug models. We found that loss of endothelial Gab1 in mice dramatically impaired postnatal angiogenesis. Gab1-ecKO mice had impaired ischemia-initiated blood flow recovery, exhibited reduced angiogenesis, and were associated with marked limb necrosis. We further observed significant endothelial cell (EC) death in the ischemic hindlimb of Gab1-ecKO mice. Matrigel plug assay showed that hepatocyte growth factor (HGF)-mediated angiogenesis was inhibited in Gab1-ecKO mice. In vitro studies showed that Gab1 was required for HGF-induced EC migration, tube formation, and microvessel sprouting. Mechanistically, HGF stimulated Gab1 tyrosine phosphorylation in ECs, leading to activation of extracellular regulated MAP kinase 1/2 and Akt, which are angiogenic and survival signaling. Conclusion- Gab1 is essential for postnatal angiogenesis through mediating angiogenic and survival signaling. Copyright © 2011 American Heart Association. All rights reserved.
Ackers-Johnson M.,University of Cambridge |
Talasila A.,University of Cambridge |
Sage A.P.,University of Cambridge |
Long X.,AAB Cardiovascular Research Institute |
And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015
Objective - Atherosclerosis, the cause of 50% of deaths in westernized societies, is widely regarded as a chronic vascular inflammatory disease. Vascular smooth muscle cell (VSMC) inflammatory activation in response to local proinflammatory stimuli contributes to disease progression and is a pervasive feature in developing atherosclerotic plaques. Therefore, it is of considerable therapeutic importance to identify mechanisms that regulate the VSMC inflammatory response. Approach and Results - We report that myocardin, a powerful myogenic transcriptional coactivator, negatively regulates VSMC inflammatory activation and vascular disease. Myocardin levels are reduced during atherosclerosis, in association with phenotypic switching of smooth muscle cells. Myocardin deficiency accelerates atherogenesis in hypercholesterolemic apolipoprotein E-/- mice. Conversely, increased myocardin expression potently abrogates the induction of an array of inflammatory cytokines, chemokines, and adhesion molecules in VSMCs. Expression of myocardin in VSMCs reduces lipid uptake, macrophage interaction, chemotaxis, and macrophage-endothelial tethering in vitro, and attenuates monocyte accumulation within developing lesions in vivo. These results demonstrate that endogenous levels of myocardin are a critical regulator of vessel inflammation. Conclusions - We propose myocardin as a guardian of the contractile, noninflammatory VSMC phenotype, with loss of myocardin representing a critical permissive step in the process of phenotypic transition and inflammatory activation, at the onset of vascular disease. © 2015 American Heart Association, Inc.
PubMed | Aab Cardiovascular Research Institute
Type: Journal Article | Journal: Journal of molecular and cellular cardiology | Year: 2011
G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multi-function scaffold protein. However, little is known about its physiological role in the heart. Here we sought to identify the cardiac function of GIT1. Global GIT1 knockout (KO) mice were generated and exhibited significant cardiac hypertrophy that progressed to heart failure. Electron microscopy revealed that the hearts of GIT1 KO mice demonstrated significant morphological abnormities in mitochondria, including decreased mitochondrial volume density, cristae density and increased vacuoles. Moreover, mitochondrial biogenesis-related gene peroxisome proliferator-activated receptor (PPAR) co-activator-1 (PGC-1), PGC-1, mitochondrial transcription factor A (Tfam) expression, and total mitochondrial DNA were remarkably decreased in hearts of GIT1 KO mice. These animals also had impaired mitochondrial function, as evidenced by reduced ATP production and dissipated mitochondrial membrane potential ((m)) in adult cardiomyocytes. Concordant with these mitochondrial observations, GIT1 KO mice showed enhanced cardiomyocyte apoptosis and cardiac dysfunction. In conclusion, our findings identify GIT1 as a new regulator of mitochondrial biogenesis and function, which is necessary for postnatal cardiac maturation.