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

Abstract

. 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...

Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats

“…Despite recent advances in redox biology and aging research (9,21,27,33,37,49,51,52,55,59,65,72,97), the role of ROS in the cerebromicrovascular effects of CR remains elusive. To assess cellular peroxide production, we used the cell-permeant oxidative fluorescent indicator dye CM-H 2DCFDA [5 (and 6)-chloromethyl-2=,7=-dichlorodihydrofluorescein diacetateacetyl ester; Invitrogen, Carlsbad, CA] as we previously reported (16,86).…”

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

“…Myocyte hypertrophy develops with advancing age (32,56). We performed hematoxylin-eosin staining and measured individual myocyte sizes for each group.…”

“…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.…”

“…Higher levels of circulating proinflammatory cytokines are observed in elderly people, even in the absence of chronic disease (3,8,16,50). In old mice, the cardiac expression of inflammatory genes increases compared with that in young mice (56). Cardiac inflammation triggers the release of fibrogenic cytokines and growth factors, leading to excessive accumulation of fibrillar collagens and adverse remodeling that, in turn, may cause cardiac dysfunction (51,54).…”

Mechanism of structural myocardial remodeling predictors determining in patients with atrial fibrillation

“…2. Патогенез розвитку та підтримки фібриляції передсердь: Ito -короткочасний ток K + з клітини; IСа -струм Ca 2+ через Ca канали L-типу; INa -струм Na + ; IKsus -неактивуючий струм K + з клітини; IК1 -випрямляючий струм K + в клітину; I K, Ach -випрямляючий струм K + в клітину, пов'язаний з G-білками, ЕРП -ефективний рефрактерний період, ДПД -довжина потенціалу дії ред ні експериментальні дослідження пока-зали, що MMП-9 має значний вплив на ремоделювання міокарду і сприяє дилатації камер і надмірному накопиченню колагену як в серцях при старінні, так і після перенесе-ного інфаркту міокарда [14,15]. Нещодавно було встановлено, що вміст MMП-9 має тісний зв'язок з ініціацією і підтримкою ФП [16].…”