Aging-Related Early Changes in Markers of Ventricular and Matrix Remodeling After Reperfused ST-Segment Elevation Myocardial Infarction in the Canine Model

Jugdutt, Bodh I.; Jelani, Anwar; Palaniyappan, Ariv; Idikio, Halliday; Uweira, Richard E.; Menon, Vijay G.; Jugdutt, Catherine

doi:10.1161/circulationaha.110.948190

Cited by 58 publications

(41 citation statements)

References 44 publications

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“…In fact, increased expression of SPARC within older mammalian hearts has been shown to contribute to increased collagen content and associated increases in stiffness indicative of the aged myocardium (6,17). Previous reports (5,26) have demonstrated the importance of SPARC in the fibrotic response to pressure overload and myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

SPARC regulates collagen interaction with cardiac fibroblast cell surfaces

Harris

Zhang²,

Card³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Harris BS, Zhang Y, Card L, Rivera LB, Brekken RA, Bradshaw AD. SPARC regulates collagen interaction with cardiac fibroblast cell surfaces. Am J Physiol Heart Circ Physiol 301: H841-H847, 2011. First published June 10, 2011; doi:10.1152/ajpheart.01247.2010.-Cardiac tissue from mice that do not express secreted protein acidic and rich in cysteine (SPARC) have reduced amounts of insoluble collagen content at baseline and in response to pressure overload hypertrophy compared with wild-type (WT) mice. However, the cellular mechanism by which SPARC affects myocardial collagen is not clearly defined. Although expression of SPARC by cardiac myocytes has been detected in vitro, immunohistochemistry of hearts demonstrated SPARC staining primarily associated with interstitial fibroblastic cells. Primary cardiac fibroblasts isolated from SPARC-null and WT mice were assayed for collagen I synthesis by [ 3 H]proline incorporation into procollagen and by immunoblot analysis of procollagen processing. Bacterial collagenase was used to discern intracellular from extracellular forms of collagen I. Increased amounts of collagen I were found associated with SPARC-null versus WT cells, and the proportion of total collagen I detected on SPARC-null fibroblasts without propeptides [collagen-␣ 1(I)] was higher than in WT cells. In addition, the amount of total collagen sensitive to collagenase digestion (extracellular) was greater in SPARC-null cells than in WT cells, indicating an increase in cell surface-associated collagen in the absence of SPARC. Furthermore, higher levels of collagen type V, a fibrillar collagen implicated in collagen fibril initiation, were found in SPARC-null fibroblasts. The absence of SPARC did not result in significant differences in proliferation or in decreased production of procollagen I by cardiac fibroblasts. We conclude that SPARC regulates collagen in the heart by modulating procollagen processing and interactions with fibroblast cell surfaces. These results are consistent with decreased levels of interstitial collagen in the hearts of SPARC-null mice being due primarily to inefficient collagen deposition into the extracellular matrix rather than to differences in collagen production. extracellular matrix; fibrosis; matricellular; osteonectin; secreted protein acidic and rich in cysteine THE COLLAGEN CONTENT of the cardiac interstitium is tightly regulated to preserve the form and function of the heart. Collagen in the healthy heart aligns myocytes and provides structural support; however, increased collagen deposition in response to myocardial infarction or in some types of cardiac hypertrophy can impair heart function (2, 18, 31). For example, an increase in collagen concentration is associated with chronic pressure overload, such as that seen in individuals with arterial hypertension, and is frequently associated with impaired diastolic function (14). The increase in cardiac collagen has been shown to be a significant contributor to greater diastolic stiffness (31). Increases in interstitial fibrill...

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Section: Discussionmentioning

confidence: 99%

SPARC regulates collagen interaction with cardiac fibroblast cell surfaces

Harris

Zhang²,

Card³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Experimental evidence supports a negative influence of age on ischemic tolerance, [5][6][7][8][9][10][11][12][13][14][15][16][17][18] and on the efficacy of cardioprotective responses in animal models 5,12,[19][20][21] and humans. [22][23][24] Dysfunctional postischemic remodeling may also arise with age.…”

Section: Introductionmentioning

confidence: 91%

“…[5][6][7][8][9][10][11][12][13][14][15][16][17] Age also impairs long-term outcomes and remodeling. 18,25 Given the predominance of ischemic heart disease in the elderly population, it is important to delineate effects of age on the heart and its response to injurious stress. With a median life span of > 800 days, 12-month C57Bl/6 mice are considered middle-aged, certainly not aged or senescent.…”

Section: Ischemic Intolerance In Ma Myocardiummentioning

confidence: 99%

“…[22][23][24] Dysfunctional postischemic remodeling may also arise with age. 18,25 Detrimental effects of age on stress resistance may involve multiple mechanisms, including alterations in stress 1 responses and signal transduction, [26][27][28] mitochondrial control of cell death, 15,26,27 autophagy, 29,30 heat shock responses, 31 and oxidative stress. 17,32 At the level of the myocardium, CR improves resistance to injurious stressors [33][34][35][36][37] and restores cytoprotective responses lost with age.…”

Section: Introductionmentioning

confidence: 99%

“…Other studies confirm age-related increases in loss of intracellular proteins. 5,12,14,15,50 Furthermore, McCully et al 16 and Jugdutt et al 18 also report age-related exaggeration of TTC-determined infarct size in vitro and in vivo. Overall, there seems to be a greater consensus regarding exaggerated contractile dysfunction with age, with mixed findings regarding markers of myocardial cell damage and death.…”

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confidence: 98%

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Opposing Effects of Age and Calorie Restriction on Molecular Determinants of Myocardial Ischemic Tolerance

Peart

Hoe

Pepe

et al. 2012

Rejuvenation Research

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We test the hypothesis that moderate calorie restriction (CR) reverses negative influences of age on molecular determinants of myocardial stress resistance. Postischemic contractile dysfunction, cellular damage, and expression of regulators of autophagy/apoptosis and of prosurvival and prodeath kinases were assessed in myocardium from young adult (YA; 2-to 4-month-old) and middle-aged (MA; 12-month-old) mice, and MA mice subjected to 14 weeks of 40% CR (MA-CR). Ventricular dysfunction after 25% -2%), as was cell death indicated by troponin I (TnI) efflux (1,701 -214 ng vs. 785 -102 ng in YA). MA hearts exhibited 30% and 65% reductions in postischemic Beclin1 and Parkin, respectively, yet 50% lower proapoptotic Bax and 85% higher antiapoptotic Bcl2, increasing the Bcl2/Bax ratio. Age did not influence Akt or p38-mitogen-activated protein kinase (MAPK) expression; reduced expression of increasingly phosphorylated ribosomal protein S6 kinase (p70S6K), increased expression of dephosphorylated glycogen synthase kinase 3b (GSK3b) and enhanced postischemic p38-MAPK phosphorylation. CR countered the age-related decline in ischemic tolerance, improving contractile recovery (60% -4%) and reducing cell death (123 -22 ng of TnI). Protection was not associated with changes in Parkin or Bax, whereas CR partially limited the age-related decline in Beclin1 and further increased Bcl2. CR counteracted age-related changes in p70S6K, increased Akt levels, and reduced p38-MAPK (albeit increasing preischemic phosphorylation), and paradoxically reduced postischemic GSK3b phosphorylation. In summary, moderate age worsens cardiac ischemic tolerance; this is associated with reduced expression of autophagy regulators, dysregulation of p70S6K and GSK3b, and postischemic p38-MAPK activation. CR counters age effects on postischemic dysfunction/cell death; this is associated with reversal of age effects on p70S6K, augmentation of Akt and Bcl2 levels, and preischemic p38-MAPK activation. Age and CR thus impact on distinct determinants of ischemic tolerance, although p70S6K signaling presents a point of convergence.

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Cardiac Physiology of Aging: Extracellular Considerations

Horn

2015

Comprehensive Physiology

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Aging is a major risk factor for the development of cardiovascular disease, with the majority of affected patients being elderly. Progressive changes to myocardial structure and function occur with aging, often in concert with underlying pathologies. However, whether chronological aging results in a remodeled "aged substrate" has yet to be established. In addition to myocyte contractility, myocardial performance relies heavily on the cardiac extracellular matrix (ECM), the roles of which are as dynamic as they are significant; including providing structural integrity, assisting in force transmission throughout the cardiac cycle and acting as a signaling medium for communication between cells and the extracellular environment. In the healthy heart, ECM homeostasis must be maintained, and matrix deposition is in balance with degradation. Consequently, alterations to, or misregulation of the cardiac ECM has been shown to occur in both aging and in pathological remodeling with disease. Mounting evidence suggests that age-induced matrix remodeling may occur at the level of ECM control; including collagen synthesis, deposition, maturation, and degradation. Furthermore, experimental studies using aged animal models not only suggest that the aged heart may respond differently to insult than the young, but the identification of key players specific to remodeling with age may hold future therapeutic potential for the treatment of cardiac dysfunction in the elderly. This review will focus on the role of the cardiac interstitium in the physiology of the aging myocardium, with particular emphasis on the implications to age-related remodeling in disease.

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Aging-Related Early Changes in Markers of Ventricular and Matrix Remodeling After Reperfused ST-Segment Elevation Myocardial Infarction in the Canine Model

Cited by 58 publications

References 44 publications

SPARC regulates collagen interaction with cardiac fibroblast cell surfaces

SPARC regulates collagen interaction with cardiac fibroblast cell surfaces

Opposing Effects of Age and Calorie Restriction on Molecular Determinants of Myocardial Ischemic Tolerance

Cardiac Physiology of Aging: Extracellular Considerations

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