Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • 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
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact

Cardiology

  • 384 Articles
  • 3 Posts
  • ← Previous
  • 1
  • 2
  • …
  • 36
  • 37
  • 38
  • 39
  • Next →
A mechanistic role for cardiac myocyte apoptosis in heart failure
Detlef Wencker, … , Robert C. Armstrong, Richard N. Kitsis
Detlef Wencker, … , Robert C. Armstrong, Richard N. Kitsis
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1497-1504. https://doi.org/10.1172/JCI17664.
View: Text | PDF

A mechanistic role for cardiac myocyte apoptosis in heart failure

  • Text
  • PDF
Abstract

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80–250 myocytes per 105 nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 105 nuclei, compared with 1.5 myocytes per 105 nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.

Authors

Detlef Wencker, Madhulika Chandra, Khanh Nguyen, Wenfeng Miao, Stavros Garantziotis, Stephen M. Factor, Jamshid Shirani, Robert C. Armstrong, Richard N. Kitsis

×

Pacemaker channel dysfunction in a patient with sinus node disease
Eric Schulze-Bahr, … , Olaf Pongs, Dirk Isbrandt
Eric Schulze-Bahr, … , Olaf Pongs, Dirk Isbrandt
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1537-1545. https://doi.org/10.1172/JCI16387.
View: Text | PDF

Pacemaker channel dysfunction in a patient with sinus node disease

  • Text
  • PDF
Abstract

The cardiac pacemaker current If is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of “idiopathic” sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide–binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated If-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac If channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient’s sinus bradycardia and the chronotropic incompetence.

Authors

Eric Schulze-Bahr, Axel Neu, Patrick Friederich, U. Benjamin Kaupp, Günter Breithardt, Olaf Pongs, Dirk Isbrandt

×

HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI–dependent manner
Ming Gong, … , Annette Uittenbogaard, Eric J. Smart
Ming Gong, … , Annette Uittenbogaard, Eric J. Smart
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1579-1587. https://doi.org/10.1172/JCI16777.
View: Text | PDF

HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI–dependent manner

  • Text
  • PDF
Abstract

Cardiovascular diseases remain the leading cause of death in the United States. Two factors associated with a decreased risk of developing cardiovascular disease are elevated HDL levels and sex — specifically, a decreased risk is found in premenopausal women. HDL and estrogen stimulate eNOS and the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, antiadhesion, and anti-inflammatory effects. We tested the hypothesis that HDL binds to its receptor, scavenger receptor class B type I (SR-BI), and delivers estrogen to eNOS, thereby stimulating the enzyme. HDL isolated from women stimulated eNOS, whereas HDL isolated from men had minimal activity. Studies with ovariectomized and ovariectomized/estrogen replacement mouse models demonstrated that HDL-associated estradiol stimulation of eNOS is SR-BI dependent. Furthermore, female HDL, but not male HDL, promoted the relaxation of muscle strips isolated from C57BL/6 mice but not SR-BI null mice. Finally, HDL isolated from premenopausal women or postmenopausal women receiving estradiol replacement therapy stimulated eNOS, whereas HDL isolated from postmenopausal women did not stimulate eNOS. We conclude that HDL-associated estrodial is capable of the stimulating eNOS. These studies establish a new paradigm for examining the cardiovascular effects of HDL and estrogen.

Authors

Ming Gong, Melinda Wilson, Thomas Kelly, Wen Su, James Dressman, Jeanie Kincer, Sergey V. Matveev, Ling Guo, Theresa Guerin, Xiang-An Li, Weifei Zhu, Annette Uittenbogaard, Eric J. Smart

×

Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A
Rita Holtwick, … , David L. Garbers, Michaela Kuhn
Rita Holtwick, … , David L. Garbers, Michaela Kuhn
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1399-1407. https://doi.org/10.1172/JCI17061.
View: Text | PDF

Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A

  • Text
  • PDF
Abstract

Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Atrial natriuretic peptide (ANP) has been postulated to exert local antihypertrophic effects in the heart. Thus, a loss of function of the ANP receptor guanylyl cyclase-A (GC-A) might contribute to the increased propensity to cardiac hypertrophy, although a causative role in vivo has not been definitively demonstrated. To test whether local ANP modulates cardiomyocyte growth, we inactivated the GC-A gene selectively in cardiomyocytes by homologous loxP/Cre-mediated recombination. Thereby we have circumvented the systemic, hypertensive phenotype associated with germline inactivation of GC-A. Mice with cardiomyocyte-restricted GC-A deletion exhibited mild cardiac hypertrophy, markedly increased mRNA expression of cardiac hypertrophy markers such as ANP (fivefold), α-skeletal actin (1.7-fold), and β-myosin heavy chain (twofold), and increased systemic circulating ANP levels. Their blood pressure was 7–10 mmHg below normal, probably because of the elevated systemic levels and endocrine actions of ANP. Furthermore, cardiac hypertrophic responses to aortic constriction were enhanced and accompanied by marked deterioration of cardiac function. This phenotype is consistent with a local function of the ANP/GC-A system to moderate the molecular program of cardiac hypertrophy.

Authors

Rita Holtwick, Martin van Eickels, Boris V. Skryabin, Hideo A. Baba, Alexander Bubikat, Frank Begrow, Michael D. Schneider, David L. Garbers, Michaela Kuhn

×

Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans
David H. McDermott, … , Dhavalkumar D. Patel, Philip M. Murphy
David H. McDermott, … , Dhavalkumar D. Patel, Philip M. Murphy
Published April 15, 2003
Citation Information: J Clin Invest. 2003;111(8):1241-1250. https://doi.org/10.1172/JCI16790.
View: Text | PDF

Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans

  • Text
  • PDF
Abstract

The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD.

Authors

David H. McDermott, Alan M. Fong, Qiong Yang, Joan M. Sechler, L. Adrienne Cupples, Maya N. Merrell, Peter W.F. Wilson, Ralph B. D’Agostino, Christopher J. O’Donnell, Dhavalkumar D. Patel, Philip M. Murphy

×

Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice
Scott P. Heximer, … , Robert P. Mecham, Kendall J. Blumer
Scott P. Heximer, … , Robert P. Mecham, Kendall J. Blumer
Published April 15, 2003
Citation Information: J Clin Invest. 2003;111(8):1259-1259. https://doi.org/10.1172/JCI15598A1.
View: Text | PDF | Amended Article

Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice

  • Text
  • PDF
Abstract

Authors

Scott P. Heximer, Russell H. Knutsen, Xiaoguang Sun, Kevin M. Kaltenbronn, Man-Hee Rhee, Ning Peng, Antonio Oliveira-dos-Santos, Josef M. Penninger, Anthony J. Muslin, Thomas H. Steinberg, J. Michael Wyss, Robert P. Mecham, Kendall J. Blumer

×

WNK kinases regulate thiazide-sensitive Na-Cl cotransport
Chao-Ling Yang, … , Rose Mitchell, David H. Ellison
Chao-Ling Yang, … , Rose Mitchell, David H. Ellison
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):1039-1045. https://doi.org/10.1172/JCI17443.
View: Text | PDF

WNK kinases regulate thiazide-sensitive Na-Cl cotransport

  • Text
  • PDF
Abstract

Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.

Authors

Chao-Ling Yang, Jordan Angell, Rose Mitchell, David H. Ellison

×

Central role of RAGE-dependent neointimal expansion in arterial restenosis
Taichi Sakaguchi, … , Ann Marie Schmidt, Yoshifumi Naka
Taichi Sakaguchi, … , Ann Marie Schmidt, Yoshifumi Naka
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):959-972. https://doi.org/10.1172/JCI17115.
View: Text | PDF

Central role of RAGE-dependent neointimal expansion in arterial restenosis

  • Text
  • PDF
Abstract

Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE’s signal transducing ligands, advanced glycation end products (AGEs) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22α promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury.

Authors

Taichi Sakaguchi, Shi Fang Yan, Shi Du Yan, Dmitri Belov, Ling Ling Rong, Monica Sousa, Martin Andrassy, Steven P. Marso, Stephan Duda, Bernd Arnold, Birgit Liliensiek, Peter P. Nawroth, David M. Stern, Ann Marie Schmidt, Yoshifumi Naka

×

The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis
Shaosong Zhang, … , Yibin Wang, Anthony J. Muslin
Shaosong Zhang, … , Yibin Wang, Anthony J. Muslin
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):833-841. https://doi.org/10.1172/JCI16290.
View: Text | PDF

The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

  • Text
  • PDF
Abstract

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the integrin-mediated activation of focal adhesion kinase and the subsequent recruitment of the Grb2 adapter molecule. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We analyzed the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Mice with haploinsufficiency of the Grb2 gene (Grb2+/– mice) appear normal at birth but have defective T cell signaling. In response to pressure overload, cardiac p38 MAPK and JNK activation was inhibited and cardiac hypertrophy and fibrosis was blocked in Grb2+/– mice. Next, transgenic mice with cardiac-specific expression of dominant negative forms of p38α (DN-p38α) and p38β (DN-p38β) MAPK were examined. DN-p38α and DN-p38β mice developed cardiac hypertrophy but were resistant to cardiac fibrosis in response to pressure overload. These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload, and that different signaling pathways downstream of Grb2 regulate fibrosis, fetal gene induction, and cardiomyocyte growth.

Authors

Shaosong Zhang, Carla Weinheimer, Michael Courtois, Attila Kovacs, Cindy E. Zhang, Alec M. Cheng, Yibin Wang, Anthony J. Muslin

×

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy
Qiujing Song, … , Gerald W. Dorn II, Evangelia G. Kranias
Qiujing Song, … , Gerald W. Dorn II, Evangelia G. Kranias
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):859-867. https://doi.org/10.1172/JCI16738.
View: Text | PDF

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

  • Text
  • PDF
Abstract

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca2+ cycling. Normalization of Ca2+ cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Gαq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-CMUT) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca2+ transients and enhanced unloaded fractional shortening with no change in SR Ca2+ pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Gαq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Gαq pathway or MyBP-C mutations.

Authors

Qiujing Song, Albrecht G. Schmidt, Harvey S. Hahn, Andrew N. Carr, Beate Frank, Luke Pater, Mike Gerst, Karen Young, Brian D. Hoit, Bradley K. McConnell, Kobra Haghighi, Christine E. Seidman, Jonathan G. Seidman, Gerald W. Dorn II, Evangelia G. Kranias

×
  • ← Previous
  • 1
  • 2
  • …
  • 36
  • 37
  • 38
  • 39
  • 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
Author's TakeCardiology

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
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts