Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

  • 479 Articles
  • 3 Posts
  • ← Previous
  • 1
  • 2
  • …
  • 37
  • 38
  • 39
  • …
  • 47
  • 48
  • Next →
Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo
YuZhen Zhang, … , George H. Rothblat, Daniel J. Rader
YuZhen Zhang, … , George H. Rothblat, Daniel J. Rader
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2870-2874. https://doi.org/10.1172/JCI25327.
View: Text | PDF

Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo

  • Text
  • PDF
Abstract

Hepatic expression of the scavenger receptor class B type I (SR-BI) promotes selective uptake of HDL cholesterol by the liver and is believed to play a role in the process of reverse cholesterol transport (RCT). We hypothesized that hepatic SR-BI expression is a regulator of the rate of integrated macrophage-to-feces RCT and used an in vivo model to test this hypothesis. Cholesterol-loaded and [3H]cholesterol-labeled J774 macrophages were injected intraperitoneally into mice, after which the appearance of the [3H]cholesterol in the plasma, liver, and feces over 48 hours was quantitated. Mice overexpressing SR-BI in the liver had significantly reduced [3H]cholesterol in the plasma but markedly increased [3H] tracer excretion in the feces over 48 hours. Conversely, mice deficient in SR-BI had significantly increased [3H]cholesterol in the plasma but markedly reduced [3H] tracer excretion in the feces over 48 hours. These studies demonstrate that hepatic SR-BI expression, despite its inverse effects on steady-state plasma HDL cholesterol concentrations, is an important positive regulator of the rate of macrophage RCT.

Authors

YuZhen Zhang, Jaqueline R. Da Silva, Muredach Reilly, Jeffrey T. Billheimer, George H. Rothblat, Daniel J. Rader

×

PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury
Tomohisa Nagoshi, … , Hunter C. Champion, Anthony Rosenzweig
Tomohisa Nagoshi, … , Hunter C. Champion, Anthony Rosenzweig
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2128-2138. https://doi.org/10.1172/JCI23073.
View: Text | PDF | Corrigendum

PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury

  • Text
  • PDF
Abstract

Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). However, less is known about the chronic effects of Akt activation in the heart, and, paradoxically, Akt is activated in samples from patients with chronic heart failure. We generated Tg mice with cardiac-specific expression of either activated (myristoylated [myr]) or dominant-negative (dn) Akt and assessed their response to IRI in an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction in functional recovery after IRI, no function was restored in any of the myr-Akt–Tg hearts. Moreover, infarcts were dramatically larger in myr-Akt–Tg hearts. Biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition of PI3K activity through both proteasome-dependent degradation of insulin receptor substrate–1 (IRS-1) and inhibition of transcription of IRS-1 as well as that of IRS-2. To test the functional significance of these signaling changes, we performed in vivo cardiac gene transfer with constitutively active PI3K in myr-Akt–Tg mice. Restoration of PI3K rescued function and reduced injury after IRI. These data demonstrate that PI3K-dependent but Akt-independent effectors are required for full cardioprotection and suggest a mechanism by which chronic Akt activation can become maladaptive.

Authors

Tomohisa Nagoshi, Takashi Matsui, Takuma Aoyama, Annarosa Leri, Piero Anversa, Ling Li, Wataru Ogawa, Federica del Monte, Judith K. Gwathmey, Luanda Grazette, Brian Hemmings, David A. Kass, Hunter C. Champion, Anthony Rosenzweig

×

Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice
Kathryn J. Moore, … , Mary McKee, Mason W. Freeman
Kathryn J. Moore, … , Mary McKee, Mason W. Freeman
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2192-2201. https://doi.org/10.1172/JCI24061.
View: Text | PDF

Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice

  • Text
  • PDF
Abstract

Macrophage internalization of modified lipoproteins is thought to play a critical role in the initiation of atherogenesis. Two scavenger receptors, scavenger receptor A (SR-A) and CD36, have been centrally implicated in this lipid uptake process. Previous studies showed that these receptors mediated the majority of cholesterol ester accumulation in macrophages exposed to oxidized LDL and that mice with deletions of either receptor exhibited marked reductions in atherosclerosis. This work has contributed to an atherosclerosis paradigm: scavenger receptor–mediated oxidized lipoprotein uptake is required for foam cell formation and atherogenesis. In this study, Apoe–/– mice lacking SR-A or CD36, backcrossed into the C57BL/6 strain for 7 generations, were fed an atherogenic diet for 8 weeks. Hyperlipidemic Cd36–/–Apoe–/– and Msr1–/–Apoe–/– mice showed significant reductions in peritoneal macrophage lipid accumulation in vivo; however, in contrast with previous reports, this was associated with increased aortic sinus lesion areas. Characterization of aortic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, indicating that lipid uptake by intimal macrophages occurs in the absence of CD36 or SR-A. These data show that alternative lipid uptake mechanisms may contribute to macrophage cholesterol ester accumulation in vivo and suggest that the roles of SR-A and CD36 as proatherosclerotic mediators of modified LDL uptake in vivo need to be reassessed.

Authors

Kathryn J. Moore, Vidya V. Kunjathoor, Stephanie L. Koehn, Jennifer J. Manning, Anita A. Tseng, Jessica M. Silver, Mary McKee, Mason W. Freeman

×

Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho
Shinji Ito, … , Yoko Nabeshima, Yo-ichi Nabeshima
Shinji Ito, … , Yoko Nabeshima, Yo-ichi Nabeshima
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2202-2208. https://doi.org/10.1172/JCI23076.
View: Text | PDF

Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho

  • Text
  • PDF
Abstract

We have generated a line of mutant mouse that lacks βKlotho, a protein that structurally resembles Klotho. The synthesis and excretion of bile acids were found to be dramatically elevated in these mutants, and the expression of 2 key bile acid synthase genes, cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1), was strongly upregulated. Nuclear receptor pathways and the enterohepatic circulation, which regulates bile acid synthesis, seemed to be largely intact; however, bile acid–dependent induction of the small heterodimer partner (SHP) NR0B2, a common negative regulator of Cyp7a1 and Cyp8b1, was significantly attenuated. The expression of Cyp7a1 and Cyp8b1 is known to be repressed by dietary bile acids via both SHP-dependent and -independent regulations. Interestingly, the suppression of Cyp7a1 expression by dietary bile acids was impaired, whereas that of Cyp8b1 expression was not substantially altered in βklotho–/– mice. Therefore, βKlotho may stand as a novel contributor to Cyp7a1-selective regulation. Additionally, βKlotho-knockout mice exhibit resistance to gallstone formation, which suggests the potential future clinical relevance of the βKlotho system.

Authors

Shinji Ito, Toshihiko Fujimori, Akiko Furuya, Junko Satoh, Yoko Nabeshima, Yo-ichi Nabeshima

×

Human cardiac potassium channel DNA polymorphism modulates access to drug-binding site and causes drug resistance
Benoit Drolet, … , Laura Mizoue, Dan M. Roden
Benoit Drolet, … , Laura Mizoue, Dan M. Roden
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2209-2213. https://doi.org/10.1172/JCI23741.
View: Text | PDF

Human cardiac potassium channel DNA polymorphism modulates access to drug-binding site and causes drug resistance

  • Text
  • PDF
Abstract

Expression of voltage-gated K+ channel, shaker-related subfamily, member 5 (KCNA5) underlies the human atrial ultra-rapid delayed rectifier K+ current (IKur). The KCNA5 polymorphism resulting in P532L in the C terminus generates IKur that is indistinguishable from wild type at baseline but strikingly resistant to drug block. In the present study, truncating the C terminus of KCNA5 generated a channel with wild-type drug sensitivity, which indicated that P532 is not a drug-binding site. Secondary structure prediction algorithms identified a probable α-helix in P532L that is absent in wild-type channels. We therefore assessed drug sensitivity of IKur generated in vitro in CHO and HEK cells by channels predicted to exhibit or lack this C-terminal α-helix. All constructs displayed near-identical IKur in the absence of drug challenge. However, those predicted to lack the C-terminal α-helix generated quinidine-sensitive currents (43–51% block by 10 μM quinidine), while the currents generated by those constructs predicted to generate a C-terminal α-helix were inhibited less than 12%. Circular dichroism spectroscopy revealed an α-helical signature with peptides derived from drug-resistant channels and no organized structure in those associated with wild-type drug sensitivity. In conclusion, we found that this secondary structure in the KCNA5 C terminus, absent in wild-type channels but generated by a naturally occurring DNA polymorphism, does not alter baseline currents but renders the channel drug resistant. Our data support a model in which this structure impairs access of the drug to a pore-binding site.

Authors

Benoit Drolet, Chantale Simard, Laura Mizoue, Dan M. Roden

×

Saturated fat–rich diet enhances selective uptake of LDL cholesteryl esters in the arterial wall
Toru Seo, … , Rajasekhar Ramakrishnan, Richard J. Deckelbaum
Toru Seo, … , Rajasekhar Ramakrishnan, Richard J. Deckelbaum
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2214-2222. https://doi.org/10.1172/JCI24327.
View: Text | PDF

Saturated fat–rich diet enhances selective uptake of LDL cholesteryl esters in the arterial wall

  • Text
  • PDF
Abstract

Plasma LDL levels and atherosclerosis both increase on a saturated fat–rich (SAT) diet. LDL cholesterol delivery to tissue may occur via uptake of the LDL particles or via selective uptake (SU), wherein cholesteryl ester (CE) enters cells without concomitant whole-particle uptake. It is not known how dietary fats might directly affect arterial LDL-CE uptake and whether SU is involved. Thus, mice that are relatively atherosclerosis resistant (C57BL/6) or susceptible to atherosclerosis (apoE–/–) were fed a chow or SAT diet and injected with double radiolabeled or fluorescent-labeled human LDL to independently trace LDL-CE core and whole-particle uptake, respectively. Our results show that a SAT diet increased contributions of SU to total arterial LDL-CE delivery in C57BL/6 and apoE–/– mice. The SAT diet increased plasma fatty acid and cholesterol levels; cholesterol, but not fatty acid, levels correlated with SU, as did the degree of atherosclerosis. Increased SU did not correlate with arterial scavenger receptor class B type I levels but paralleled increased lipoprotein lipase (LPL) levels and LPL distribution in the arterial wall. These studies suggest that arterial LDL-CE delivery via SU can be an important mechanism in vivo and that dietary influences on arterial LPL levels and atherogenesis modulate arterial LDL-CE delivery, cholesterol deposition, and SU.

Authors

Toru Seo, Kemin Qi, Chuchun Chang, Ying Liu, Tilla S. Worgall, Rajasekhar Ramakrishnan, Richard J. Deckelbaum

×

FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes
Nathalie Rosenblatt-Velin, … , Friedrich Beermann, Thierry Pedrazzini
Nathalie Rosenblatt-Velin, … , Friedrich Beermann, Thierry Pedrazzini
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1724-1733. https://doi.org/10.1172/JCI23418.
View: Text | PDF

FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes

  • Text
  • PDF
Abstract

Recent evidence suggests that the heart possesses a greater regeneration capacity than previously thought. In the present study, we isolated undifferentiated precursors from the cardiac nonmyocyte cell population of neonatal hearts, expanded them in culture, and induced them to differentiate into functional cardiomyocytes. These cardiac precursors appear to express stem cell antigen–1 and demonstrate characteristics of multipotent precursors of mesodermal origin. Following infusion into normal recipients, these cells home to the heart and participate in physiological and pathophysiological cardiac remodeling. Cardiogenic differentiation in vitro and in vivo depends on FGF-2. Interestingly, this factor does not control the number of precursors but regulates the differentiation process. These findings suggest that, besides its angiogenic actions, FGF-2 could be used in vivo to facilitate the mobilization and differentiation of resident cardiac precursors in the treatment of cardiac diseases.

Authors

Nathalie Rosenblatt-Velin, Mario G. Lepore, Cristina Cartoni, Friedrich Beermann, Thierry Pedrazzini

×

Liver X receptors α and β regulate renin expression in vivo
Fulvio Morello, … , Richard E. Pratt, Victor J. Dzau
Fulvio Morello, … , Richard E. Pratt, Victor J. Dzau
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1913-1922. https://doi.org/10.1172/JCI24594.
View: Text | PDF

Liver X receptors α and β regulate renin expression in vivo

  • Text
  • PDF
Abstract

The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor α (LXRα) and LXRβ in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXRα functioned as a cAMP-activated factor, LXRβ was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXRα was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXRα to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXRα–/– mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXRβ–/– mice exhibited reduced kidney renin mRNA levels compared with controls. LXRα–/–LXRβ–/– mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXRα and LXRβ regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXRα signaling pathway is required for the adrenergic control of the renin-angiotensin system.

Authors

Fulvio Morello, Rudolf A. de Boer, Knut R. Steffensen, Massimiliano Gnecchi, Jeffrey W. Chisholm, Frans Boomsma, Leonard M. Anderson, Richard M. Lawn, Jan-Åke Gustafsson, Marco Lopez-Ilasaca, Richard E. Pratt, Victor J. Dzau

×

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog
Nitish R. Mahapatra, … , John Ross Jr., Sushil K. Mahata
Nitish R. Mahapatra, … , John Ross Jr., Sushil K. Mahata
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1942-1952. https://doi.org/10.1172/JCI24354.
View: Text | PDF

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog

  • Text
  • PDF
Abstract

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release–inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga–/– and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga–/– mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga–/– mice. Loss of the physiological “brake” catestatin in Chga–/– mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.

Authors

Nitish R. Mahapatra, Daniel T. O’Connor, Sucheta M. Vaingankar, Amiya P. Sinha Hikim, Manjula Mahata, Saugata Ray, Eugenie Staite, Hongjiang Wu, Yusu Gu, Nancy Dalton, Brian P. Kennedy, Michael G. Ziegler, John Ross Jr., Sushil K. Mahata

×

Morphogenesis of the right ventricle requires myocardial expression of Gata4
Elisabeth M. Zeisberg, … , Seigo Izumo, William T. Pu
Elisabeth M. Zeisberg, … , Seigo Izumo, William T. Pu
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1522-1531. https://doi.org/10.1172/JCI23769.
View: Text | PDF

Morphogenesis of the right ventricle requires myocardial expression of Gata4

  • Text
  • PDF
Abstract

Mutations in developmental regulatory genes have been found to be responsible for some cases of congenital heart defects. One such regulatory gene is Gata4, a zinc finger transcription factor. In order to circumvent the early embryonic lethality of Gata4-null embryos and to investigate the role of myocardial Gata4 expression in cardiac development, we used Cre/loxP technology to conditionally delete Gata4 in the myocardium of mice at an early and a late time point in cardiac morphogenesis. Early deletion of Gata4 by Nkx2-5Cre resulted in hearts with striking myocardial thinning, absence of mesenchymal cells within the endocardial cushions, and selective hypoplasia of the RV. RV hypoplasia was associated with downregulation of Hand2, a transcription factor previously shown to regulate formation of the RV. Cardiomyocyte proliferation was reduced, with a greater degree of reduction in the RV than in the LV. Late deletion of Gata4 by Cre recombinase driven by the α myosin heavy chain promoter did not selectively affect RV development or generation of endocardial cushion mesenchyme but did result in marked myocardial thinning with decreased cardiomyocyte proliferation, as well as double-outlet RV. Our results demonstrate a general role of myocardial Gata4 in regulating cardiomyocyte proliferation and a specific, stage-dependent role in regulating the morphogenesis of the RV and the atrioventricular canal.

Authors

Elisabeth M. Zeisberg, Qing Ma, Amy L. Juraszek, Kelvin Moses, Robert J. Schwartz, Seigo Izumo, William T. Pu

×
  • ← Previous
  • 1
  • 2
  • …
  • 37
  • 38
  • 39
  • …
  • 47
  • 48
  • Next →
Calpain-6 mediates atherogenic macrophage function
In this episode, Takuro Miyazaki and colleagues reveal that elevation of calpain-6 in macrophages promotes atherogenic functions by disrupting CWC22/EJC/Rac1 signaling.
Published August 15, 2016
Video AbstractsCardiology

Kruppel-like factor 4 keeps the heart healthy
Xudong Liao and colleagues identify KLF4 as an important regulator of mitochondrial development and function in the heart…
Published August 4, 2015
Scientific Show StopperCardiology

Oxidation impedes cardioprotection
Taishi Nakamura and colleagues reveal that oxidation prevents the beneficial effects of PKG1α in response to cardiac stress…
Published May 4, 2015
Scientific Show StopperCardiology
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts