Copper-induced reduction in myocardial fibrosis is associated with increased matrix metalloproteins in a rat model of cardiac hypertrophy

Chen

et al. 2018

Exp Biol Med (Maywood)

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Dietary copper supplementation reverses pressure overload-induced cardiac hypertrophy by copper replenishment in the heart. A copper-selective chelator, trientine (triethylenetetramine [TETA]), reverses left ventricular hypertrophy associated with diabetes also by copper replenishment in the heart. The present study was undertaken to address the critical issue how TETA delivers copper to the heart. Adult male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Eight weeks after the TAC surgery, cardiac hypertrophy was developed and copper content in the heart was reduced. TETA was then administrated by gavage in two different dosages (21.9 or 87.6 mg/kg day) for six weeks. The results showed that in the lower dosage, TETA replenished copper contents in the heart, along with a decrease in the copper concentration in the blood and kidney, and an increase in the urine. In the higher dosage, TETA did not replenish copper contents in the heart, but markedly increased copper concentrations in the urine and decreased those in the blood and kidney. Neither lower nor higher TETA dosage altered copper concentrations in other organs. Corresponding to myocardial copper replenishment, the lower dose TETA suppresses cardiac hypertrophy, as judged by a reduction in the left ventricle wall thickness and a decrease in the heart size, and diminished cardiac fibrosis, as reflected by a decrease in collagen I content. TETA in the higher dose not only did not suppress cardiac hypertrophy, but also caused cardiac hypertrophy in sham-operated rats. TETA-mediated myocardial copper restoration is independent of copper transporter-1 or -2 but related to an energy-dependent transportation. This study demonstrates that low-dose TETA functions as a copper chaperone, selectively delivering copper to the copper-deprived heart through an active transportation; in higher doses, TETA simply retains its chelator function, removing copper from the body by urinary excretion. Impact statement Our study reveals that TETA, traditionally regarded as a copper chelator, in lower doses delivers copper selectively to the heart through a mechanism independent of copper transporter-1 or -2. Copper supplementation by a lower dose of TETA suppresses pressure overload-induced cardiac hypertrophy. Since ischemic heart disease and hypertrophic cardiomyopathy are accompanied by myocardial copper loss, this approach of using a lower dose of TETA to supplement copper to the heart would help treat the disease condition of patients with such cardiac events.

Section: Discussionmentioning

confidence: 99%

Trientine selectively delivers copper to the heart and suppresses pressure overload-induced cardiac hypertrophy in rats

Chen

et al. 2018

Exp Biol Med (Maywood)

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“…Formation of scar tissue is closely associated with depressed angiogenesis, constituting a natural barrier for myocardial regeneration. 6 Promotion of angiogenesis activates multiple cytokines including matrix metalloproteinases (MMPs), 96,97 which are responsible for degradation of collagens. In the process of copper-induced angiogenesis, the fibrotic scar is also ameliorated, due to an increase of MMP-2 protein level and activity in the heart.…”

Section: Angiogenesis In Myocardial Regenerationmentioning

confidence: 99%

Copper promotion of myocardial regeneration

Xiao

Wang

Song

et al. 2020

Exp Biol Med (Maywood)

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Myocardial regeneration is the key to the functional recovery of ischemic heart. Angiogenesis plays a pivotal role in myocardial regeneration by resetting a rejuvenation microenvironment under ischemic conditions. Hypoxia-inducible factor 1 (HIF-1) is the predominant transcription factor in the regulation of angiogenesis. In prolonged myocardial infarction, HIF-1α, the critical subunit of HIF-1, is accumulated in the infarcted myocardium, but fails to activate angiogenesis, suggesting a missing of a critical factor in the HIF-1 regulation of angiogenesis. Copper is involved in multiple steps of HIF-1 regulation of target gene expression. However, copper is deprived during myocardial ischemic injury, leading to deactivation of HIF-1-regulated angiogenesis. Multiple approaches are applied to increasing copper availability in the ischemic heart, effectively reactivating transcription of HIF-1 target angiogenic genes. Copper-induced angiogenesis thus reconstructs the conduit for the transduction of tissue injury signaling, recruitment of tissue repair materials such as stem cells, and the homing of stem cells, leading to the promotion of myocardial regeneration. Thus, copper promotes myocardial regeneration through reactivation of HIF-1-regulated angiogenesis. This would constitute an alternative therapeutic approach to ischemic heart disease. Impact statement Copper promotes angiogenesis, but the mechanistic insights have not been fully elucidated until recently. In addition, the significance of copper promotion of angiogenesis in myocardial regeneration was increasingly revealed. Copper critically participates in the regulation of hypoxia-inducible factor 1 (HIF-1) of angiogenic gene expression. Interestingly, myocardial ischemia causes copper efflux from the heart, leading to suppression of angiogenesis, although HIF-1α, the critical subunit of HIF-1, remains accumulated in the ischemic myocardium. Strategies targeting copper specific delivery to the ischemic myocardium lead to selective activation of HIF-1-regulated angiogenic gene expression. Vascularization of the ischemic myocardium re-establishes the tissue injury microenvironment, and rebuilds the conduit for communication between the tissue injury signals and the remote regenerative responses including stem cells. This process promotes myocardial regeneration. Thus, a simple and effective copper supplementation to the ischemic myocardium would become a novel therapeutic approach to the treatment of patients with ischemic heart diseases.

“…Коллагены I и III типа, составляющие 90% массы ЭЦМ миокарда, из всех ММП наиболее активно расщепляются ММП-1, что обусловливает интерес к данной молекуле в контексте фибротического ремоделирования [36,37]. Основными источниками ММП-1 являются лейкоциты, фибробласты и эндотелиальные клетки [38,39]. В сыворотке крови пациентов, перенесших ИМ и подвергшихся реперфузионной терапии, MMП-1 увеличивается через 5 дней, достигая максимальной концентрации к 14 дню и снижаясь до нормы к 28 дню после ИМ [38,39].…”

Section: биомаркеры фиброза миокарда и их генетическое регулированиеunclassified

“…Основными источниками ММП-1 являются лейкоциты, фибробласты и эндотелиальные клетки [38,39]. В сыворотке крови пациентов, перенесших ИМ и подвергшихся реперфузионной терапии, MMП-1 увеличивается через 5 дней, достигая максимальной концентрации к 14 дню и снижаясь до нормы к 28 дню после ИМ [38,39].…”

Section: биомаркеры фиброза миокарда и их генетическое регулированиеunclassified

“…В сыворотке крови ММП-9 увеличивается уже на первые сутки после ИМ и остается повышенным до 7 сут., при этом высокий уровень ММП-9 является предиктором неблагоприятного сердечно-сосудистого исхода независимо от уровня других маркеров воспаления [36]. Также было продемонстрировано, что увеличение ММП-9 коррелирует с увеличением объема ЛЖ и более выраженной его дисфункцией после ИМ [35][36][37][38][39]. ММП-9-опосредованная деградация скевенджер-рецептора CD36 приводит к снижению эффективности фагоцитоза, увеличению продолжительности воспаления и как следствие к увеличению ЛЖ после ИМ [35][36][37][38][39].…”

Section: биомаркеры фиброза миокарда и их генетическое регулированиеunclassified

See 1 more Smart Citation

Biomarkers of myocardial fibrosis and their genetic regulation in patients with heart failure

Печерина

Kutikhin

2020

Russ J Cardiol

Currently, the development of chronic heart failure (CHF) is considered from the perspective of pathological structural remodeling of myocardium and fibrosis. Despite the widespread use of molecular genetic markers in clinical practice, only a small number of them are used to evaluate remodeling processes, as well as to predict potential complications associated with heart failure (HF). In addition, the relationship between many biomarkers with instrumental and histological confirmation of myocardial fibrosis has not yet been determined. Myocardial fibrosis remains quite debatable and controversial subject, which actualizes the further study of this direction. The discovery of pathogenetic and diagnostic markers of myocardial fibrosis could contribute to the development of targeted therapy. Of particular interest is the search for possible pathogenetic markers, since this is relevant for clinical practice.