Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice

Jiang, Youchun; Reynolds, Corey; Xiao, Chang; Feng, Wenke; Zhou, Zhanxiang; Rodríguez, Walter; Tyagi, Suresh C.; Eaton, John W.; Saari, Jack T.; Kang, Y. James

doi:10.1084/jem.20061943

Cited by 153 publications

(175 citation statements)

References 30 publications

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“…Previous studies in vivo have shown that dietary Cu supplementation-induced regression of hypertrophic cardiomyopathy was partially mediated by VEGF-dependent angiogenesis [1]. To determine the role of VEGF in the direct effect of Cu on cardiomyocyte hypertrophy, an anti-VEGF antibody at a final concentration of 2 ng/ml was added before the addition of 5 μM Cu element in the PE-treated cultures.…”

Section: Cu-induced Reduction In Cell Size Was Vegf-dependentmentioning

confidence: 99%

“…Previous studies have shown that dietary supplementation with physiologically relevant levels of copper (Cu) reversed pressure overload-induced cardiac hypertrophy in a mouse model along with a complete recovery of the contractile function of the heart [1]. Although the regression of cardiac hypertrophy by dietary copper supplementation in humans is unknown, a recent study in a small population of chronic heart failure patients has shown that dietary supplementation with micronutrients for 9 months increased left ventricle ejection, decreased left ventricle volume, and improved the quality of life [2].…”

Section: Introductionmentioning

confidence: 99%

“…Vascular endothelial growth factor (VEGF) is a critical growth factor for the regulation of angiogenesis and promotes blood vessel formation in the recovery of tissue injury [6,7]. During the transition from cardiac hypertrophy to heart failure, VEGF levels in the heart are suppressed [1,4]. Interestingly, the regression of cardiac hypertrophy induced by dietary Cu supplementation is VEGF-dependent; systemic administration of anti-VEGF antibody completely blocks Cu supplementation-induced regression of heart hypertrophy [1].…”

Section: Introductionmentioning

confidence: 99%

“…During the transition from cardiac hypertrophy to heart failure, VEGF levels in the heart are suppressed [1,4]. Interestingly, the regression of cardiac hypertrophy induced by dietary Cu supplementation is VEGF-dependent; systemic administration of anti-VEGF antibody completely blocks Cu supplementation-induced regression of heart hypertrophy [1]. Because VEGF promotes blood vessel formation and the anti-VEGF antibody blocks the angiogenesis, the regression of heart hypertrophy was considered angiogenesis-dependent.…”

Section: Introductionmentioning

confidence: 99%

“…Through a thorough analysis of cell cycle and mitotic activities of the cardiomyocytes in cultures under different conditions in combination with the analysis of cell size, the contribution of the reduction in the size of individual hypertrophied cardiomyocytes to the regression of heart hypertrophy can be determined. Therefore, the present study has two purposes: (1) to determine the direct effect of Cu on the regression of cardiac hypertrophy and (2) to define the cellular basis of regression of cardiac hypertrophy. The results obtained demonstrated that Cu causes a direct reduction in the size of hypertrophied cardiomyocytes and this effect is VEGF dependent.…”

Section: Introductionmentioning

confidence: 99%

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Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Zhou

Jiang

Kang

2008

Journal of Molecular and Cellular Cardiology

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Previous studies have shown that dietary copper supplementation reversed heart hypertrophy induced by pressure overload in a mouse model. The present study was undertaken to understand the cellular basis of copper-induced regression of cardiac hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine at a final concentration of 100 μM in cultures for 48 h to induce cellular hypertrophy. The hypertrophied cardiomyocytes were exposed to copper sulfate at a final concentration of 5 μM in cultures for additional 24 h. This copper treatment reduced the size of the hypertrophied cardiomyocytes, as measured by flow cytometry, protein content in cells, cell volume and cardiomyocyte hypertrophy markers including beta myosin heavy chain protein, skeletal alpha-actin, and atrial natriuretic peptide. Cell cycle analysis and cell sorting of p-histone-3 labeled cardiomyocytes indicated that cell division was not involved in the copper-induced regression of cardiomyocyte hypertrophy. Copper also inhibited PE-induced apoptosis, determined by a TUNEL assay. Because copper stimulates vascular endothelial growth factor (VEGF) production through activation of hypoxia-inducible transcription factor, an anti-VEGF antibody at a final concentration of 2 ng/ml in cultures was used and shown to blunt copper-induced regression of cell hypertrophy. Conversely, VEGF alone at a final concentration of 0.2 μg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF dependent.

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Section: Cu-induced Reduction In Cell Size Was Vegf-dependentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Zhou

Jiang

Kang

2008

Journal of Molecular and Cellular Cardiology

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Modulation of AHR Function by Heavy Metals and Disease States

Anwar‐Mohammed

El‐Kadi

2011

The AH Receptor in Biology and Toxicology

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Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

Hsu

2021

Advanced Biology

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Pharmacotherapy has been serving as an effective treatment for HFs to improve symptom, functional capacity, quality of life, and to reduce the frequency of hospitalizations. [8] However, it differs in each HF subtype. Traditionally, angiotensin converting enzyme inhibitors (ACEIs), mineralocorticoid receptor antagonists (MRAs), and β-blockers are typical treatments for HFrEF. Since many hospitalizations and deaths in HFpEF patients are due to noncardiovascular causes, pharmacotherapy mainly focus on relieving of symptoms and easing comorbidities for HFpEF patients.HFpEF with a prevalence range from 31% to 55% has received most attention recently from the clinical and research field [4,9,10] due to lack of effective pharmacological treatment options. Although cardiac regenerative therapeutics have been widely studied in the past two decades [11] for treating both HFrEF and HFpEF, the treatment mechanisms and associated intrinsic cardiac remodeling process are nonspecific to each HF subtype. Besides, additional mechanisms such as metabolic disorders, proinflammatory conditions, and immunologic remodeling also influenced the prognosis of different HFs. [12] In this review, we summarized pathological cardiac remodeling, associated immune reactions, and signaling pathways for HF in general, and discussed the challenges that hamper clinical translation of regenerative therapeutics which holds diagnostic and therapeutic potential. This review helps to reveal the underlying mechanisms that may lead us to generate new clinical-feasible treatment for HFpEF in the future. [13][14][15][16][17][18] Signaling during HF Progression HF ProgressionThe growth of cardiomyocytes occurs in both physiological and pathological hypertrophy. [19] Physiologically, hemodynamic load stimulates normal, postnatal, pregnancy, and exercise-induced cardiac growth. [19] Pathologically, the stimulation from HF risk factors increases heart size, mass, or geometry. In the progression of HF, multiple molecular mechanisms associated with cardiomyocyte survival, death, energy metabolism, oxidative stress, inflammation, calcium transport and neurohormonal activation led to loss of functional cardiomyocytes, development of fibrosis, left ventricular remodeling, and HF prognosis. [20] Heart failure (HF) is one of the leading causes for hospital admissions worldwide. HF patients are classified based on the chronic changes in left ventricular ejection fraction (LVEF) as preserved (LVEF ≥ 50%), reduced (LVEF ≤ 40%), or mid-ranged (40% < LVEF < 50%) HFs. Treatments nowadays can prevent HFrEF progress, whereas only a few of the treatments have been proven to be effective in improving the survival of HFpEF. In this review, numerous mediators involved in the pathogenesis of HF are summarized. The regional upstream signaling and their diagnostic and therapeutic potential are also discussed. Additionally, the recent challenges and development in cardiac regenerative therapy that hold opportunities for future research and clinical translation are discussed.

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Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice

Cited by 153 publications

References 30 publications

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Modulation of AHR Function by Heavy Metals and Disease States

Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

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