Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice

Chiao, Ying Ann; Ramirez, Trevi A.; Zamilpa, Rogelio; Okoronkwo, S. Michelle; Dai, Qiuxia; Zhang, Jianhua; Jin, Yu; Lindsey, Merry L.

doi:10.1093/cvr/cvs275

Cited by 154 publications

(139 citation statements)

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“…Inflammatory cytokines are important contributors to cardiac aging (12,56). To assess whether SPARC mediates cardiac inflammation, we measured the LV expression of inflammatory cytokines and receptors by gene array (Fig.…”

Section: Sparc Expression Increased With Age In LVmentioning

confidence: 99%

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

Toba

Brás

Baicu

et al. 2015

American Journal of Physiology-Cell Physiology

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Toba H, de Castro Brás LE, Baicu CF, Zile MR, Lindsey ML, Bradshaw AD. Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization. Am J Physiol Cell Physiol 308: C972-C982, 2015. First published April 15, 2015; doi:10.1152/ajpcell.00402.2014.-To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in age-related cardiac inflammation, we studied six groups of mice: young (3-5 mo old), middle-aged (10 -12 mo old), and old (18 -29 mo old) C57BL/6 wild-type (WT) and SPARC-null (Null) mice (n ϭ 7-10/group). Cardiac function and structure were determined by echocardiography. The left ventricle was used for cytokine gene array and macrophage quantification by immunohistochemistry. Macrophage infiltration increased with age in WT (n ϭ 5-6/group, P Ͻ 0.05 for young vs. old), but not in Null. Proinflammatory markers (Ccl5, Cx3cl1, Ccr2, and Cxcr3) increased in middle-aged and old WT, whereas they were increased only in old Null compared with respective young (n ϭ 5-6/group, P Ͻ 0.05 for all). These results suggest that SPARC deletion delayed age-related cardiac inflammation. To further assess how SPARC affects inflammation, we stimulated peritoneal macrophages with SPARC (n ϭ 4). SPARC treatment increased expression of proinflammatory macrophage M1 markers and decreased anti-inflammatory M2 markers. Echocardiography (n ϭ 7-10/group) revealed an age-related increase in wall thickness of the left ventricle in WT (0.76 Ϯ 0.02 mm in young vs. 0.91 Ϯ 0.03 mm in old; P Ͻ 0.05) but not in Null (0.78 Ϯ 0.01 mm in young vs. 0.84 Ϯ 0.02 mm in old). In conclusion, SPARC deletion delayed age-related increases in macrophage infiltration and proinflammatory cytokine expression in vivo and in vitro. SPARC acts as an important mediator of age-related cardiac inflammation by increasing the expression of macrophage M1 markers and decreasing M2 markers.

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Section: Sparc Expression Increased With Age In LVmentioning

confidence: 99%

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

Toba

Brás

Baicu

et al. 2015

American Journal of Physiology-Cell Physiology

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“…Adult C57BL/6J WT (n ϭ 20, 10 male and 10 female) and Null (n ϭ 21, 10 male and 11 female) mice of 15-18 mo of age were compared. We also compared the 15-18-moold mice to young 6 -9-mo-old WT (n ϭ 12, 6 male and 6 female) and Null (n ϭ 12, 7 male and 5 female) mice that were a randomly selected subgroup from our previous study (7). The previous acquired echocardiography and Doppler data were combined with new gene array, histology, and protein expression results obtained on the tissuebanked samples collected for these mice as well as new samples collected for this study.…”

Section: Micementioning

confidence: 99%

“…We have shown that MMP-9 expression increases with age, concomitant with the development of diastolic dysfunction in wild-type (WT) mice after 18 mo of age (7). This decline in diastolic function was attenuated by MMP-9 deletion in old and senescent mice.…”

mentioning

confidence: 99%

“…In mice, aging associates with a subtle but significant decline in function of the left ventricle (LV) (21). Altered LV function is characterized by the development of diastolic dysfunction, as systolic function remains relatively unchanged (7). The cardiac extracellular matrix (ECM) regulates LV diastolic properties, provides structural support for the myocardium, and incorporates homeostatic elements such as growth factors (16).…”

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confidence: 99%

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Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Yabluchanskiy

Chiao

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. Am J Physiol Heart Circ Physiol 306: H1398 -H1407, 2014. First published March 21, 2014; doi:10.1152/ajpheart.00090.2014Aging is linked to increased matrix metalloproteinase-9 (MMP-9) expression and extracellular matrix turnover, as well as a decline in function of the left ventricle (LV). Previously, we demonstrated that C57BL/6J wild-type (WT) mice Ͼ 18 mo of age show impaired diastolic function, which was attenuated by MMP-9 deletion. To evaluate mechanisms that initiate the development of cardiac dysfunction, we compared the LVs of 6 -9-and 15-18-mo-old WT and MMP-9 null (Null) mice. All groups showed similar LV function by echocardiography, indicating that dysfunction had not yet developed in the older group. Myocyte nuclei numbers and cross-sectional areas increased in both WT and Null 15-18-mo mice compared with young controls, indicating myocyte hypertrophy. Myocyte hypertrophy leads to an increased oxygen demand, and both WT and Null 15-18-mo mice showed an increase in angiogenic signaling. Plasma proteomic profiling and LV analysis revealed a threefold increase in von Willebrand factor and fivefold increase in vascular endothelial growth factor in WT 15-18-mo mice, which were further elevated in Null mice. In contrast to the upregulation of angiogenic stimulating factors, actual LV vessel numbers increased only in the 15-18-mo Null LV. The 15-18-mo WT showed amplified expression of inflammatory genes related to angiogenesis, including C-C chemokine receptor (CCR)7, CCR10, interleukin (IL)-1f8, IL-13, and IL-20 (all, P Ͻ 0.05), and these increases were blunted by MMP-9 deletion (all, P Ͻ 0.05). To measure vascular permeability as an index of endothelial function, we injected mice with FITC-labeled dextran. The 15-18-mo WT LV showed increased vascular permeability compared with young WT controls and 15-18-mo Null mice. Combined, our findings revealed that MMP-9 deletion improves angiogenesis, attenuates inflammation, and prevents vascular leakiness in the setting of cardiac aging.aging; inflammation; angiogenesis; MMP-9; proteomics; extracellular matrix AGING IS A MAJOR RISK FACTOR for cardiac mortality and morbidity (11, 30). Elderly patients with acute cardiovascular disease have poor clinical outcomes. Aging is associated with alterations in homeostatic mechanisms that make the vasculature more susceptible to damaging effects of pathophysiological conditions (35). Aging impairs diastolic function in humans, independent of existing comorbidities such as hypertension (18). In mice, aging associates with a subtle but significant decline in function of the left ventricle (LV) (21). Altered LV function is characterized by the development of diastolic dysfunction, as systolic function remains relatively unchanged (7). The cardiac extracellular matrix (ECM) regulates LV diastolic properties, provides structural support for the myocardium, and incorporates homeostatic elements such as growth factors (16). Matrix metal...

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“…Металлопротеиназы всегда рассматривались как ферменты деградации межклеточного матрикса. Однако ММР-9 является профиброгенным факто-ром, поскольку обеспечивает процессинг латентной формы TGF-β, переводя его в активную форму, ини-циирующую рост соединительной ткани [8][9][10]. Повышенный уровень синтеза ММP-9 макрофагами в миокарде может указывать на интенсивный фибрил-логенез в зоне ишемии, формирование и экспансию рубца (рис.…”

Section: литератураunclassified

Metalloproteases and Inhibitors Expression in Myocardium Under Ischemic Conditions After Allogenic Biomaterial Introduction

et al. 2018

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ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯВозможность стимуляции кардиомиогенеза постишемического миокарда до сих пор остается актуальной задачей. Как правило, формированию рубца в мышечной ткани способствует стремитель-ное накопление стромальных элементов и низкая скорость или отсутствие репликации мышечных кле-ток [1]. Изучение кардиопротекторных механизмов в ишемически поврежденной сердечной мышечной ткани позволяет обосновать и оптимизировать стра-тегию её восстановления и нивелировать рубец. Цель. Определить уровни экспрессии ММР-9 и TIMP-2 после интрамиокарди-ального введения аллогенного биоматериала (БМА) в ишемизированный миокард крыс. Материал и методы. Использовали 100 крыс породы Вистар, которым осу-ществляли лигирование коронарной артерии. В опытной группе (n=50) одно-временно с коронароокклюзией вводили суспензию БМА в количестве 12 мг. Применяли общегистологические исследования: окраска гематоксилином и эозином, по Маллори; иммуногистохимические (ММP-9, TIMP-2, CD68); мор-фометрические: определение индекса площади рубца (ИПР), количество ММP-9, TIMP-2, CD68 позитивных клеток; статистические. Результаты. Показано, что в опытной группе после имплантации БМА наблю-дались меньшие, чем в контроле: значения ИПР (в 2,74 раза p<0,05 ÷ <0,0001), численность MMP9 + клеток (p<0,001) и макрофагов CD68 + (p<0,05), а также манифестация протеолитических процессов и размер зоны поражения. Напротив, количество Timp-2 + клеток в опытной группе был выше, чем в конт-рольной группе (p<0,0004). Заключение. Продукты резорбции аллогенного биоматериала Аллоплант влияют на баланс металлопротеиназ и их ингибиторов в миокарде после ише-мического повреждения. Этот эффект способен оказать значительное влия-ние на процессы ремоделирования миокарда и формирование рубца. ЭКСПРЕССИЯ МЕТАЛЛОПРОТЕИНАЗ И ИХ ИНГИБИТОРОВ В ИШЕМИЗИРОВАННОМ МИОКАРДЕ ПОСЛЕ ПРИМЕНЕНИЯ АЛЛОГЕННОГО БИОМАТЕРИАЛА METALLOPROTEASES AND INHIBITORS ExPRESSION IN MYOCARDIUM UNDER ISCHEMIC CONDITIONS AFTER ALLOGENIC BIOMATERIAL INTRODUCTIONLebedeva A. I.

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Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice

Abstract: MMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.

Cited by 154 publications

References 38 publications

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Metalloproteases and Inhibitors Expression in Myocardium Under Ischemic Conditions After Allogenic Biomaterial Introduction

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