Adiponectin Deficiency, Diastolic Dysfunction, and Diastolic Heart Failure

Sam, Flora; Duhaney, Toni-Ann S.; Sato, Kaori; Wilson, Richard; Ohashi, Koji; Sono-Romanelli, Saki; Higuchi, Akiko; Silva, Deepa S. De; Qin, Fuzhong; Walsh, Kenneth; Ouchi, Noriyuki

doi:10.1210/en.2009-0806

Cited by 79 publications

(82 citation statements)

References 66 publications

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“…Consistent with these findings, our data indicate that APN (in addition to ameliorating LVH) protected against the development of fibrosis and limited matrix remodeling in response to ANG II infusion in vivo by suppressing expression of MMP-2 and MMP-9. There was no effect on TIMP expression, the endogenous inhibitors of MMPs, which is in agreement with our prior findings in aldosterone-infused APN-KO hearts (47). Therefore, the increased MMP-to-TIMP ratio seen in ANG IIinfused APN-KO hearts is a measure of net MMP activation and results in an MMP/TIMP stoichiometry that would favor increased myocardial matrix degradation and a prolonged/persistent matrix proteolytic state.…”

Section: Apn Ameliorates the Effects Of Ros On Cardiac Remodelingsupporting

confidence: 91%

Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling

Essick¹,

Ouchi²,

Wilson³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 g/ml, 18 h) followed by exposure to physiologic concentrations of H2O2 (1-200 M). ARVM hypertrophy was measured by [ 3 H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg·kg Ϫ1 ·day Ϫ1 for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H2O2-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H2O2-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H2O2-treated ARVM. H 2O2-induced p-ERK activity and NF-B activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-B activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROSinduced cardiac remodeling. reactive oxygen species; adenosine 5=-monophosphate-activated protein kinase; matrix metalloproteinase; cardiomyocyte hypertrophy

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Section: Apn Ameliorates the Effects Of Ros On Cardiac Remodelingsupporting

confidence: 91%

Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling

Essick¹,

Ouchi²,

Wilson³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

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“…11 Aldosterone has also been shown in a few studies to act through GRs to mediate genomic or nongenomic effects. [31][32][33][34] The aldosterone-GR pathway has also been observed in cardiomyocytes, and has been related to hypertrophy. 35 Moreover, in a study using cardiac fibroblast-specific MR knockout mice, cardiac fibrosis was not reduced in pressure-overload conditions.…”

Section: Discussionmentioning

confidence: 99%

“…44 In a study using aldosterone infusion in mice, the group receiving aldosterone infusion was associated with a higher degree of cardiac fibrosis and diastolic dysfunction as assessed using the E/E′ ratio. 34 MR blockers have been used to treat patients with heart failure with diastolic dysfunction, and this treatment reduced diastolic dysfunction and improved exercise capacity. 6,7 However, in a large clinical trial, the outcomes were not significantly improved after MR blockade treatment.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Induces Tissue Inhibitor of Metalloproteinases-1 Expression and Further Contributes to Collagen Accumulation

et al. 2016

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Abstract-Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity.

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“…Genetic deletion of other factors in mice, such as apoptosis signalregulating kinase 1 (ASK1), growth arrest specific protein 6 (GAS6), and NADPH-oxidase 2 (Nox2), has been shown to modulate aldosterone-induced cardiovascular damage (48)(49)(50)(51). In all of these prior studies, mice were infused with a high dose of aldosterone (or deoxycorticosterone, the major murine mineralocorticoid) and fed a high-salt diet and/or underwent uninephrectomy, which resulted in significant hypertension.…”

Section: Figurementioning

confidence: 99%