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

Abstract

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...

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

“…However, the magnitude of increase in calcineurin signaling was not similar to that observed in DOCA-salt male WT mice. Similar changes in collagen type I and III expression profiles and perivascular fibrosis have been observed in hearts of ovariectomized rats exposed to volume overload after aortocaval shunt, 31 implicating the importance of estrogen-mediated signals for protecting against eccentric cardiac hypertrophy and fibrosis. Thus, intact ER␤ could not only attenuate activation of mediators of maladaptive hypertrophy but also could be important for the maintenance of protective signals controlling their activation.…”

Estrogen Replacement Therapy and Cardiac Function Under Metabolic Syndrome

“…These findings support the notion that estrogen limits undesirable extracellular matrix remodeling and ventricular dilation in volume-overloaded hearts. 8 Similarly, female mice were found resistant to deoxycorticosterone acetate-salt-induced cardiac hypertrophy through estrogen receptor-induced adaptive stress signaling activation and inhibition of maladaptive calcineurin signaling in deoxycorticosterone acetate-treated female mice. 7 Therefore, ERT may exert distinctive effects under different physiological/ pathological conditions.…”

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Biochemical aspects of gender differences in response to cardiac resynchronization therapy

“…Однако нельзя исключить, что кардиоактивные эффекты половых гормонов на физиологические про-цессы в миокарде могут оказывать влияние на исходы СРТ. В литературе описана способность половых гормо-нов оказывать как противовоспалительный эффект [42], так и кардиопротективное действие на состояние ЭКМ [43][44][45]. Необходимы дальнейшие исследования в этом направлении.…”