Activation of Matrix Metalloproteinases Precedes Left Ventricular Remodeling in Hypertensive Heart Failure Rats

Sakata, Yasushi; Yamamoto, Kazuhide; Mano, Toshiaki; Nishikawa, Nagahiro; Yoshida, Junichi; Hori, Masatsugu; Miwa, Takeshi; Masuyama, Tohru

doi:10.1161/01.cir.0000125741.88712.77

Cited by 156 publications

(138 citation statements)

References 33 publications

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“…MMP 2 and 9 expression has been shown to be enhanced in pressure-overloaded cardiac hypertrophy in spontaneously hypertensive rats 3 and in Dahl salt-sensitive hypertensive rats. 4 Similar upregulation of MMPs has been also observed in human pressure-overloaded hearts because of aortic stenosis. 5 Recently, Heymans et al 6 have demonstrated that MMP 9 is involved in cardiac remodeling associated with hypertension.…”

supporting

confidence: 52%

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

et al. 2006

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Abstract-Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (nϭ10) and sibling wild-type (WT) mice (nϭ9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.

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supporting

confidence: 52%

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

et al. 2006

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“…22,38 Our finding that EPL attenuated the increase in the MMP/TIMP ratio suggests that activation of mineralocorticoid receptors contributes to LV dilation in response to pressure overload. Despite LV dilation and an increase in the MMP/TIMP ratio, pressure overload was associated with increased interstitial and perivascular fibrosis, similar to that described by Rocha et al 11 and Sun et al 12 in rats subjected to chronic aldosterone infusion.…”

Section: Mineralocorticoid Receptors Mediate Interstitial Matrix Remomentioning

confidence: 87%

“…18 Mineralocorticoid receptors affect MMP activity, 10,21 and ACE inhibition suppresses MMP activation and prevents LV remodeling and dysfunction. 22 Thus, it is possible that aldosterone, acting via the mineralocorticoid receptors, is involved in mediating at least some of the cellular events observed in pressure overloadinduced myocardial failure.…”

mentioning

confidence: 99%

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

et al. 2005

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Background-Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results-We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4Ϯ0.1 versus 3.7Ϯ0.1 mm) and end-systolic (2.0Ϯ0.1 versus 2.5Ϯ0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42Ϯ2% versus 34Ϯ4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions-Mineralocorticoid

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“…Portions of the RNA (2 mg) were subjected to reverse transcription (RT) with the use of random primers (Invitrogen, Carlsbad, CA, USA) and MuLV Reverse Transcriptase (Applied Biosystems, Foster City, CA, USA). The resulting complementary DNA was subjected to real-time PCR analysis with the use of a Prism 7700 Sequence Detector (Perkin-Elmer, Waltham, MA, USA), as previously described, 23 and with primers and TaqMan probes specific for atrial natriuretic peptide (ANP), 22 brain natriuretic peptide (BNP), 22 collagen type I 24 or type III, 24 angiotensin-converting enzyme (ACE), 22 the AT 1A 22 or AT 2 (5¢-CTGGCTGTGGCTGACTTACTC-3¢, 5¢-TTTGC ACATCACAGGTCCAAAG-3¢, and 5¢-TTGGCAACCCTTCCTCTCTGGGCA-3¢ as the forward primer, reverse primer and TaqMan probe, respectively; GenBank accession no. NM_022456) receptor, transforming growth factorb1 (TGF-b1) 22 or connective tissue growth factor (CTGF).…”

Section: Quantitative Rt-pcr Analysismentioning

confidence: 99%

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension

et al. 2011

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Although thiazide diuretics are commonly used to supplement angiotensin receptor blockers for treatment of hypertension, the mechanism underlying the therapeutic effects of this drug combination remains unclear. We investigated the antihypertensive and cardioprotective effects of combination therapy with losartan (LOS) and hydrochlorothiazide (HCTZ), in comparison with those of either drug alone, in Dahl salt-sensitive hypertensive rats. Rats fed a high-salt diet from 6 weeks of age were treated with LOS, HCTZ, both drugs (COMB) and vehicle from 6 to 11 weeks. The salt-induced increase in systolic blood pressure was attenuated moderately by LOS and to a greater extent by HCTZ and COMB. Left ventricular (LV) hypertrophy and fibrosis, diastolic dysfunction, as well as angiotensin-converting enzyme and angiotensin II type 1A (AT 1A ) receptor gene expression were attenuated similarly by LOS and HCTZ and more so by COMB. LOS downregulated expression of the AT 1A receptor gene, without affecting that of the AT 2 receptor gene, in the aorta. In contrast, neither HCTZ nor COMB affected aortic expression of the AT 1A receptor gene, but both markedly upregulated that of the AT 2 receptor gene. The salt-induced decrease in the plasma concentration of nitric oxide metabolites was attenuated substantially by LOS and abolished by both HCTZ and COMB. In conclusion, the combination of LOS and HCTZ attenuated hypertension, as well as LV remodeling and diastolic dysfunction, more effectively than did LOS or HCTZ alone in rats with salt-sensitive hypertension. Modulation of the cardiac and vascular renin-angiotensin system may have contributed to these beneficial effects of the drug combination.

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Activation of Matrix Metalloproteinases Precedes Left Ventricular Remodeling in Hypertensive Heart Failure Rats

Cited by 156 publications

References 33 publications

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension

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