Person: Bloch, Donald
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Bloch
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Bloch, Donald
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Publication MicroRNA-425 and microRNA-155 cooperatively regulate atrial natriuretic peptide expression and cGMP production(Public Library of Science, 2018) Vandenwijngaert, Sara; Ledsky, Clara D.; Agha, Obiajulu; Wu, Connie; Hu, Dongjian; Bagchi, Aranya; Domian, Ibrahim; Buys, Emmanuel; Newton-Cheh, Christopher; Bloch, DonaldAims Atrial natriuretic peptide (ANP), secreted primarily by atrial cardiomyocytes, decreases blood pressure by raising cyclic 3’,5’-guanosine monophosphate (cGMP) levels and inducing vasorelaxation, natriuresis, and diuresis. Raising the level of ANP has been shown to be an effective treatment for hypertension. To advance the future development of an anti-microRNA (miR) approach to increasing expression of ANP, we investigated the regulation of NPPA expression by two miRs: miR-425 and miR-155. We examined whether miR-425 and miR-155 have an additive effect on the expression and function of ANP. Methods and results Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were transfected with miR-425, miR-155, or a combination of the two miRs. Two days later, NPPA expression was measured using real time qPCR. Each of the miRs decreased NPPA expression over a wide range of concentrations, with a significant reduction at concentrations as low as 1 nM. The combination of miR-425 and miR-155 reduced NPPA expression to a greater extent than either miR-425 or miR-155 alone. An in vitro assay was developed to study the potential biological significance of the miR-induced decrease in NPPA expression. The cooperative effect of miR-425 and miR-155 on NPPA expression was associated with a significant decrease in cGMP levels. Conclusions: These data demonstrate that miR-425 and miR-155 regulate NPPA expression in a cooperative manner. Targeting both miRNAs with anti-miRs (possibly at submaximal concentrations) might prove to be a more effective strategy to modulate ANP levels, and thus blood pressure, than targeting either miRNA alone.Publication The Ability of Nitric Oxide to Lower Intraocular Pressure Is Dependent on Guanylyl Cyclase(The Association for Research in Vision and Ophthalmology, 2017) Muenster, Stefan; Lieb, Wolfgang S.; Fabry, Gregor; Allen, Kaitlin N.; Kamat, Shivani S.; Guy, Ann H.; Dordea, Ana C.; Teixeira, Leandro; Tainsh, Robert E.; Yu, Binglan; Zhu, Wei; Ashpole, Nicole E.; Malhotra, Rajeev; Brouckaert, Peter; Bloch, Donald; Scherrer-Crosbie, Marielle; Stamer, W. Daniel; Kuehn, Markus H.; Pasquale, Louis; Buys, EmmanuelPurpose While nitric oxide (NO) donors are emerging as treatments for glaucoma, the mechanism by which NO lowers intraocular pressure (IOP) is unclear. NO activates the enzyme guanylyl cyclase (GC) to produce cyclic guanosine monophosphate. We studied the ocular effects of inhaled and topically applied NO gas in mice and lambs, respectively. Methods: IOP and aqueous humor (AqH) outflow were measured in WT and GC-1α subunit null (GC-1−/−) mice. Mice breathed 40 parts per million (ppm) NO in O2 or control gas (N2/O2). We also studied the effect of ocular NO gas exposure (80, 250, 500, and 1000 ppm) on IOP in anesthetized lambs. NO metabolites were measured in AqH and plasma. Results: In awake WT mice, breathing NO for 40 minutes lowered IOP from 14.4 ± 1.9 mm Hg to 10.9 ± 1.0 mm Hg (n = 11, P < 0.001). Comparable results were obtained in anesthetized WT mice (n = 10, P < 0.001). In awake or anesthetized GC-1−/− mice, IOP did not change under similar experimental conditions (P ≥ 0.08, n = 20). Breathing NO increased in vivo outflow facility in WT but not GC-1−/− mice (+13.7 ± 14.6% vs. −12.1 ± 9.4%, n = 4 each, P < 0.05). In lambs, ocular exposure to NO lowered IOP in a dose-dependent manner (−0.43 mm Hg/ppm NO; n = 5 with 40 total measurements; P = 0.04) without producing corneal pathology or altering pulmonary and systemic hemodynamics. After ocular NO exposure, NO metabolites were increased in AqH (n = 8, P < 0.001) but not in plasma. Conclusions: Breathing NO reduced IOP and increased outflow facility in a GC-dependent manner in mice. Exposure of ovine eyes to NO lowers IOP.Publication Deletion of the Sequence Encoding the Tail Domain of the Bone Morphogenetic Protein type 2 Receptor Reveals a Bone Morphogenetic Protein 7-Specific Gain of Function(Public Library of Science, 2013) Leyton, Patricio A.; Beppu, Hideyuki; Pappas, Alexandra; Martyn, Trejeeve M.; Derwall, Matthias; Baron, David M.; Galdos, Rita; Bloch, Donald; Bloch, KennethThe bone morphogenetic protein (BMP) type II receptor (BMPR2) has a long cytoplasmic tail domain whose function is incompletely elucidated. Mutations in the tail domain of BMPR2 are found in familial cases of pulmonary arterial hypertension. To investigate the role of the tail domain of BMPR2 in BMP signaling, we generated a mouse carrying a Bmpr2 allele encoding a non-sense mediated decay-resistant mutant receptor lacking the tail domain of Bmpr2. We found that homozygous mutant mice died during gastrulation, whereas heterozygous mice grew normally without developing pulmonary arterial hypertension. Using pulmonary artery smooth muscle cells (PaSMC) from heterozygous mice, we determined that the mutant receptor was expressed and retained its ability to transduce BMP signaling. Heterozygous PaSMCs exhibited a BMP7‑specific gain of function, which was transduced via the mutant receptor. Using siRNA knockdown and cells from conditional knockout mice to selectively deplete BMP receptors, we observed that the tail domain of Bmpr2 inhibits Alk2‑mediated BMP7 signaling. These findings suggest that the tail domain of Bmpr2 is essential for normal embryogenesis and inhibits Alk2‑mediated BMP7 signaling in PaSMCs.Publication MicroRNA miR-425 is a negative regulator of atrial natriuretic peptide(BioMed Central, 2013) Arora, Pankaj; Wu, Connie; Bloch, Donald; Davis-Dusenbury, Brandi N; Spagnolli, Ester; Hata, Akiko; Vandenwijngaert, Sara; Swinnen, Melissa; Janssens, Stefan; Buys, Emmanuel; Bloch, Kenneth; Newton-Cheh, Christopher; Wang, Thomas Jue-FuuPublication Consensus Statement on the Pathology of IgG4-Related Disease(Nature Publishing Group, 2012) Deshpande, Vikram; Zen, Yoh; Chan, John KC; Yi, Eunhee E; Sato, Yasuharu; Yoshino, Tadashi; Klöppel, Günter; Heathcote, J Godfrey; Khosroshahi, Arezou; Ferry, Judith; Aalberse, Rob C; Bloch, Donald; Brugge, William; Bateman, Adrian C; Carruthers, Mollie Nicole; Chari, Suresh T; Cheuk, Wah; Cornell, Lynn D; Fernandez-Del Castillo, Carlos; Forcione, David; Hamilos, Daniel; Kamisawa, Terumi; Kasashima, Satomi; Kawa, Shigeyuki; Kawano, Mitsuhiro; Lauwers, Gregory Y.; Masaki, Yasufumi; Nakanuma, Yasuni; Notohara, Kenji; Okazaki, Kazuichi; Ryu, Ji Kon; Saeki, Takako; Sahani, Dushyant; Smyrk, Thomas C; Stone, James; Takahira, Masayuki; Webster, George J; Yamamoto, Motohisa; Zamboni, Giuseppe; Umehara, Hisanori; Stone, JohnIgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.Publication LMKB/MARF1 Localizes to mRNA Processing Bodies, Interacts with Ge-1, and Regulates IFI44L Gene Expression(Public Library of Science, 2014) Bloch, Donald; Li, Pingcheng; Bloch, Emily G.; Berenson, Daniel F.; Galdos, Rita L.; Arora, Pankaj; Malhotra, Rajeev; Wu, Connie; Yang, WeihongThe mRNA processing body (P-body) is a cellular structure that regulates the stability of cytoplasmic mRNA. MARF1 is a murine oocyte RNA-binding protein that is associated with maintenance of mRNA homeostasis and genomic stability. In this study, autoantibodies were used to identify Limkain B (LMKB), the human orthologue of MARF1, as a P-body component. Indirect immunofluorescence demonstrated that Ge-1 (a central component of the mammalian core-decapping complex) co-localized with LMKB in P-bodies. Two-hybrid and co-immunoprecipitation assays were used to demonstrate interaction between Ge-1 and LMKB. The C-terminal 120 amino acids of LMKB mediated interaction with Ge-1 and the N-terminal 1094 amino acids of Ge-1 were required for interaction with LMKB. LMKB is the first protein identified to date that interacts with this portion of Ge-1. LMKB was expressed in human B and T lymphocyte cell lines; depletion of LMKB increased expression of IFI44L, a gene that has been implicated in the cellular response to Type I interferons. The interaction between LMKB/MARF1, a protein that contains RNA-binding domains, and Ge-1, which interacts with core-decapping proteins, suggests that LMKB has a role in the regulation of mRNA stability. LMKB appears to have different functions in different cell types: maintenance of genomic stability in developing oocytes and possible dampening of the inflammatory response in B and T cells.Publication Inhibition of Bone Morphogenetic Protein Signal Transduction Prevents the Medial Vascular Calcification Associated with Matrix Gla Protein Deficiency(Public Library of Science, 2015) Malhotra, Rajeev; Burke, Megan F.; Martyn, Trejeeve; Shakartzi, Hannah R.; Thayer, Timothy E.; O’Rourke, Caitlin; Li, Pingcheng; Derwall, Matthias; Spagnolli, Ester; Kolodziej, Starsha A.; Hoeft, Konrad; Mayeur, Claire; Jiramongkolchai, Pawina; Kumar, Ravindra; Buys, Emmanuel; Yu, Paul; Bloch, Kenneth D.; Bloch, DonaldObjective: Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice. Approach and Results MGP-deficient mice (MGP-/-) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP-/- mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP-/- mice survived longer than vehicle-treated MGP-/- mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP-/- and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP-/- aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189. Conclusions: Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP-/- mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice.Publication Atrial natriuretic peptide is negatively regulated by microRNA-425(American Society for Clinical Investigation, 2013) Arora, Pankaj; Wu, Connie; Khan, Abigail May; Bloch, Donald; Davis-Dusenbery, Brandi N; Ghorbani, Anahita; Spagnolli, Ester; Martinez, Andrew; Ryan, Allicia; Tainsh, Laurel T.; Kim, Samuel M; Rong, Jian; Huan, Tianxiao; Freedman, Jane E.; Levy, Daniel; Miller, Karen; Hata, Akiko; Del Monte, Federica; Vandenwijngaert, Sara; Swinnen, Melissa; Janssens, Stefan; Holmes, Tara M.; Buys, Emmanuel; Bloch, Kenneth; Newton-Cheh, Christopher; Wang, Thomas Jue-FuuNumerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.Publication Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice(Mary Ann Liebert Inc, 2017) Vandenwijngaert, Sara; Swinnen, Melissa; Walravens, Ann-Sophie; Beerens, Manu; Gillijns, Hilde; Caluwé, Ellen; Tainsh, Robert; Nathan, Daniel I.; Allen, Kaitlin; Brouckaert, Peter; Bartunek, Jozef; Scherrer-Crosbie, Marielle; Bloch, Kenneth; Bloch, Donald; Janssens, Stefan P.; Buys, EmmanuelAims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC a1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCa1 allele [sGCa1-/-CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCa1-/-CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCa1 mutant (DNsGCa1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCa1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCa1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCa1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCa1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity.Publication Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation(MyJove Corporation, 2016) O'Rourke, Caitlin; Shelton, Georgia; Hutcheson, Joshua; Burke, Megan F.; Martyn, Trejeeve; Thayer, Timothy E.; Shakartzi, Hannah R.; Buswell, Mary D.; Tainsh, Robert; Yu, Binglan; Bagchi, Aranya; Rhee, David Kwan; Wu, Connie; Derwall, Matthias; Buys, Emmanuel; Yu, Paul; Bloch, Kenneth; Aikawa, Elena; Bloch, Donald; Malhotra, RajeevCardiovascular disease is the leading cause of morbidity and mortality in the world. Atherosclerotic plaques, consisting of lipid-laden macrophages and calcification, develop in the coronary arteries, aortic valve, aorta, and peripheral conduit arteries and are the hallmark of cardiovascular disease. In humans, imaging with computed tomography allows for the quantification of vascular calcification; the presence of vascular calcification is a strong predictor of future cardiovascular events. Development of novel therapies in cardiovascular disease relies critically on improving our understanding of the underlying molecular mechanisms of atherosclerosis. Advancing our knowledge of atherosclerotic mechanisms relies on murine and cell-based models. Here, a method for imaging aortic calcification and macrophage infiltration using two spectrally distinct near-infrared fluorescent imaging probes is detailed. Near-infrared fluorescent imaging allows for the ex vivo quantification of calcification and macrophage accumulation in the entire aorta and can be used to further our understanding of the mechanistic relationship between inflammation and calcification in atherosclerosis. Additionally, a method for isolating and culturing animal aortic vascular smooth muscle cells and a protocol for inducing calcification in cultured smooth muscle cells from either murine aortas or from human coronary arteries is described. This in vitro method of modeling vascular calcification can be used to identify an characterize the signaling pathways likely important for the development of vascular disease, in the hopes of discovering novel targets for therapy.