Person:
Bloch, Kenneth

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Bloch

First Name

Kenneth

Name

Bloch, Kenneth
Author's Publications: search.filters.isAuthorOfPublication.a13b41b2-7f5a-4b36-9063-a46e44dc9e3e

Search Results

Now showing 1 - 10 of 29
  • Thumbnail Image
    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, Kenneth
    The 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.
  • Thumbnail Image
    Publication
    Phosphomimetic Modulation of eNOS Improves Myocardial Reperfusion and Mimics Cardiac Postconditioning in Mice
    (Public Library of Science, 2014) Pong, Terrence; Scherrer-Crosbie, Marielle; Atochin, Dmitriy; Bloch, Kenneth; Huang, Paul
    Objective: Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. Methods and Results: We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. Conclusions and Significance Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.
  • Thumbnail Image
    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-Fuu
  • Thumbnail Image
    Publication
    Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation
    (Springer Nature, 2007) Beppu, Hideyuki; Mwizerwa, O N; Beppu, Y; Dattwyler, M P; Lauwers, Gregory Y.; Bloch, Kenneth; Goldstein, Allan
    Stromal–epithelial interactions play a central role in development and tumorigenesis. Bone morphogenetic protein (BMP) signaling in the intestine is involved in both of these processes. Inactivation of BMP pathway genes in the epithelium is known to cause intestinal polyposis. However, the role of the intestinal stroma in polyp initiation is incompletely understood. We observed that conditional inactivation of the BMP type II receptor (BMPRII) in the stroma leads to epithelial hyperplasia throughout the colon with increased epithelial cell proliferation. Mutant mice developed rectal bleeding and hamartomatous polyps in the colorectum. The polyps demonstrated increased proliferation of epithelial and mesenchymal cells in the mucosa with an expansion of the myofibroblast cell population. These results demonstrate that genetic mutations altering the BMP signaling pathway in the stromal microenvironment can lead to epithelial tumors in the colon.
  • Thumbnail Image
    Publication
    Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice
    (American Society for Clinical Investigation, 2012) Buys, Emmanuel; Raher, Michael J.; Kirby, Andrew; Mohd, Shahid; Baron, David; Hayton, Sarah R.; Tainsh, Laurel T.; Sips, Patrick; Rauwerdink, Kristen M.; Yan, Qingshang; Tainsh, Robert; Shakartzi, Hannah R.; Stevens, Christine; Decaluwé, Kelly; Rodrigues-Machado, Maria da Gloria; Malhotra, Rajeev; Van de Voorde, Johan; Wang, Tong; Brouckaert, Peter; Daly, Mark; Bloch, Kenneth
    Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα1), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα1 deficiency. This region is syntenic with previously identified blood pressure–related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-deficient mice. These data identify the RAAS as a blood pressure–modifying mechanism in a setting of impaired NO/cGMP signaling.
  • Thumbnail Image
    Publication
    Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance
    (American Physiological Society, 2011) Kurtz, Baptiste; Thibault, Helene B.; Raher, Michael J.; Popovich, John R.; Cawley, Sharon; Atochin, Dmitriy; Hayton, Sarah; Shakartzi, Hannah R.; Huang, Paul; Bloch, Kenneth; Buys, Emmanuel; Scherrer-Crosbie, Marielle
    Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.
  • Thumbnail Image
    Publication
    In Vivo Noninvasive Characterization of Brown Adipose Tissue Blood Flow by Contrast Ultrasound in Mice
    (Ovid Technologies (Wolters Kluwer Health), 2012) Baron, David M.; Clerte, Maeva; Brouckaert, Peter; Raher, Michael J.; Flynn, Aidan W.; Zhang, Haihua; Carter, Edward; Picard, Michael; Bloch, Kenneth; Buys, Emmanuel; Scherrer-Crosbie, Marielle
    Background—Interventions to increase brown adipose tissue (BAT) volume and activation are being extensively investigated as therapies to decrease the body weight in obese subjects. Noninvasive methods to monitor these therapies in animal models and humans are rare. We investigated whether contrast ultrasound (CU) performed in mice could detect BAT and measure its activation by monitoring BAT blood flow. After validation, CU was used to study the role of uncoupling protein 1 and nitric oxide synthases in the acute regulation of BAT blood flow. Methods and Results—Blood flow of interscapular BAT was assessed in mice (n=64) with CU by measuring the signal intensity of continuously infused contrast microbubbles. Blood flow of BAT estimated by CU was 0.5±0.1 (mean±SEM) dB/s at baseline and increased 15-fold during BAT stimulation by norepinephrine (1 µg·kg−1·min−1). Assessment of BAT blood flow using CU was correlated to that performed with fluorescent microspheres (R2=0.86, P<0.001). To evaluate whether intact BAT activation is required to increase BAT blood flow, CU was performed in uncoupling protein 1–deficient mice with impaired BAT activation. Norepinephrine infusion induced a smaller increase in BAT blood flow in uncoupling protein 1–deficient mice than in wild-type mice. Finally, we investigated whether nitric oxide synthases played a role in acute norepinephrine-induced changes of BAT blood flow. Genetic and pharmacologic inhibition of nitric oxide synthase 3 attenuated the norepinephrine-induced increase in BAT blood flow. Conclusions—These results indicate that CU can detect BAT in mice and estimate BAT blood flow in mice with functional differences in BAT.
  • Thumbnail Image
    Publication
    Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene
    (Elsevier BV, 2011) Steinbicker, Andrea U.; Liu, Heling; Jiramongkolchai, Kim; Malhotra, Rajeev; Choe, Elizabeth Y.; Busch, Cornelius J.; Graveline, Amanda; Kao, Sonya M.; Nagasaka, Yasuko; Ichinose, Fumito; Buys, Emmanuel; Brouckaert, Peter; Zapol, Warren; Bloch, Kenneth
    Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca2+) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca2+ channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca2+ signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca2+ in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel cross-talk mechanism between cGMP and cAMP signaling pathways.
  • Thumbnail Image
    Publication
    Effects of transdermal testosterone on natriuretic peptide levels in women: a randomized placebo-controlled pilot study
    (Elsevier BV, 2012) Lin, Eleanor; McCabe, Elizabeth; Newton-Cheh, Christopher; Bloch, Kenneth; Buys, Emmanuel; Wang, Thomas Jue-Fuu; Miller, Karen
    Objective: To investigate whether testosterone administration alters natriuretic peptide levels in women. Design: Three-month, double-blind, randomized, placebo-controlled study. Setting: Clinical research center. Patient(s): Fifty-one women with hypoandrogenemia due to hypopituitarism. Intervention(s): Transdermal testosterone (300 μg daily) or placebo patch. Main Outcome Measure(s): N-Terminal pro–B-type natriuretic peptide (NT-proBNP) levels. Result(s): NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months. The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model assessment of insulin resistance. Change in NT-proBNP over 3 months was inversely associated with change in free testosterone levels. Conclusion(s): Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system. Clinical Trials Registration Number: NCT00027430.
  • Thumbnail Image
    Publication
    Pathophysiology of Hypertension in the Absence of Nitric Oxide/Cyclic GMP Signaling
    (Springer Science + Business Media, 2012) Thoonen, Robrecht; Sips, Patrick; Bloch, Kenneth; Buys, Emmanuel
    The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling system is a well-characterized modulator of cardiovascular function, in general, and blood pressure, in particular. The availability of mice mutant for key enzymes in the NO-cGMP signaling system facilitated the identification of interactions with other blood pressure modifying pathways (e.g. the renin-angiotensin-aldosterone system) and of gender-specific effects of impaired NO-cGMP signaling. In addition, recent genome-wide association studies identified blood pressure-modifying genetic variants in genes that modulate NO and cGMP levels. Together, these findings have advanced our understanding of how NO-cGMP signaling regulates blood pressure. In this review, we will summarize the results obtained in mice with disrupted NO-cGMP signaling and highlight the relevance of this pathway as a potential therapeutic target for the treatment of hypertension.