Effects of Early and Late Chronic Pressure Overload on Extracellular Matrix Remodeling

Lin, Jing Ying; Davis, Harrison; Dai, Quixia; Chou, Youn Min; Craig, Teresa; Hinojosa‐Laborde, Carmen; Lindsey, Merry L.

doi:10.1291/hypres.31.1225

Cited by 28 publications

(30 citation statements)

References 21 publications

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“…Our data agree with previous reports that demonstrate the association of decreased TIMP-1 expression and heart failure in humans (29,54). Similar results were found in hearts of aged ovariectomized rats (30). Further, estrogen treatment restored TIMP-1 expression and TIMP-1/ MMP-9 balance in VOX rat hearts, to levels found in intact VO.…”

Section: Discussionsupporting

confidence: 93%

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Voloshenyuk

Gardner

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Our previous studies demonstrate that 17␤-estradiol limits chronic volume overload-induced hypertrophy and improves heart function in ovariectomized rats. One possible cardioprotective mechanism involves the interaction between estrogen, estrogen receptors, and proteins of the extracellular matrix (ECM). The impact of estrogen deficiency and replacement on left ventricular (LV) hypertrophy and ECM protein expression was studied using five female rat groups: intact sham-operated, ovariectomized sham-operated, intact with volume overload, ovariectomized with volume overload, and ovariectomized with volume overload treated with estrogen. After 8 wk, LV protein extracts were evaluated by Western blot analysis for matrix metalloproteinase-2 (MMP-2) and MMP-9, MT1-MMP, tissue inhibitors of MMPs (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4, collagens type I and III, and estrogen receptor ␣ and ␤ expression. MMP proteolytic activity was assessed by zymography. All volume-overloaded groups exhibited LV hypertrophy, which was associated with a loss of interstitial collagen and perivascular fibrosis. After 8 wk of volume overload, 70% of ovariectomized rats developed heart failure, in contrast to only one intact rat. A downregulation of MMP-2, estrogen receptor-␣ (ER␣), and ER␤, and upregulation of MMP-9 and MT1-MMP were found in the volume-overloaded hearts of ovariectomized rats. Estrogen treatment improved TIMP-2/MMP-2 and TIMP-1/MMP-9 protein balance, restored ER␣ expression, and prevented MMP-9 activation, perivascular collagen accumulation and development of heart failure. However, estrogen did not fully restore ER␤ expression and did not prevent the increase of MMP-9 expression or loss of interstitial collagen. These results support that estrogen limits undesirable ECM remodeling and LV dilation, in part, through modulation of ECM protein expression in volume-overloaded hearts of ovariectomized rats. extracellular matrix remodeling; ovariectomy; gender; hypertrophy; hormone; collagen; MT1-MMP; ventricle THE RISKS AND BENEFITS ASSOCIATED with estrogen replacement therapy remain uncertain. Conflicting results regarding the effect of estrogen replacement on the outcome of cardiovascular disease have been obtained from population studies, animal models, and clinical trials (2,16,20,21,32,33,61). The inconsistency of these findings demonstrates the lack of understanding of the mechanisms by which estrogen exerts its beneficial effects on the cardiovascular system. Using a rodent model, we demonstrated that hearts of intact female rats are resistant to chronic volume overload-induced adverse cardiac remodeling and dysfunction (12). This apparent cardioprotection is lost following ovariectomy (6). Estrogen replacement delays the development of left ventricular (LV) hypertrophy and dilation, and it prevents the onset of congestive heart failure (CHF) in ovariectomized rats with volume overload (13). However, the mechanisms of estrogen's protective effects in prevention of adverse myocardial remodeling remain unclear.Changes in extra...

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Section: Discussionsupporting

confidence: 93%

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Voloshenyuk

Gardner

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…By contrast, in the current study, rather than a persistent and progressive pattern, MT1-MMP promoter activation, expression, and activity appear to follow a time-dependent pattern following PO. In at least one other study, MT1-MMP abundance was increased following PO (23). Data presented in the study of Lin et al (23) serve to support and are largely concordant with the results of the current study.…”

Section: Effects Of Mt1-mmp On LV Structural Remodelingsupporting

confidence: 91%

Pressure overload-dependent membrane type 1-matrix metalloproteinase induction: relationship to LV remodeling and fibrosis

Zile¹,

Baicu²,

Stroud

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Increased myocardial extracellular matrix collagen represents an important structural milestone during the development of left ventricular (LV) pressure overload (PO); however, the proteolytic pathways that contribute to this process are not fully understood. This study tested the hypothesis that membrane type 1-matrix metalloproteinase (MT1-MMP) is directly induced at the transcriptional level in vivo during PO and is related to changes in LV collagen content. PO was induced in vivo by transverse aortic constriction in transgenic mice containing the full length human MT1-MMP promoter region ligated to luciferase (MT1-MMP Prom mice). MT1-MMP promoter activation (luciferase expression), expression, and activity; collagen volume fraction (CVF); and left atrial dimension were measured at 1 (n = 8), 2 (n = 12), and 4 (n = 17) wk following PO. Non-PO mice (n = 10) served as controls. Luciferase expression increased by fivefold at 1 wk, fell at 2 wk, and increased again by ninefold at 4 wk of PO (P < 0.05). MT1-MMP expression and activity increased at 1 wk, fell at 2 wk, and increased again at 4 wk after PO. CVF increased at 1 wk, remained unchanged at 2 wk, and increased by threefold at 4 wk of PO (P < 0.05). There was a strong positive correlation between CVF and MT1-MMP activity (r = 0.80, P < 0.05). Left atrial dimension remained unchanged at 1 and 2 wk but increased by 25% at 4 wk of PO. When a mechanical load was applied in vitro to LV papillary muscles isolated from MT1-MMP Prom mice, increased load caused MT1-MMP promoter activation to increase by twofold and MT1-MMP expression to increase by fivefold (P < 0.05). These findings challenge the canonical belief that PO suppresses overall matrix proteolytic activity, but rather supports the concept that certain proteases, such as MT1-MMP, play a pivotal role in PO-induced matrix remodeling and fibrosis.

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“…3 The resultant pathological changes seen include myocyte hypertrophy, local fibroblast proliferation and alterations in the myocardial extracellular matrix. 4,5 It is widely accepted that blood pressure control is central in the prevention of the adverse effects of hypertension on the cardiovascular system. Furthermore, some recent studies have suggested that the use of antihypertensive therapies that modulate the renin-angiotensin system appears to afford a superior clinical benefit to that provided by blood pressure control alone.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

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Effects of Early and Late Chronic Pressure Overload on Extracellular Matrix Remodeling

Cited by 28 publications

References 21 publications

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Pressure overload-dependent membrane type 1-matrix metalloproteinase induction: relationship to LV remodeling and fibrosis

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

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