Adiponectin deficiency, diastolic dysfunction, and diastolic heart failure - PubMed (original) (raw)

Adiponectin deficiency, diastolic dysfunction, and diastolic heart failure

Flora Sam et al. Endocrinology. 2010 Jan.

Abstract

Aldosterone infusion results in left ventricular hypertrophy (LVH) and hypertension and may involve profibrotic and proinflammatory mechanisms. In turn, hypertension is the major cause of diastolic heart failure (HF). Adiponectin, an adipose-derived plasma protein, exerts antiinflammatory and anti-hypertrophic effects and is implicated in the development of hypertension and systolic HF. We thus tested the hypothesis that hypoadiponectinemia in aldosterone-induced hypertension exacerbated cardiac remodeling and diastolic HF. Wild-type (WT) or adiponectin-deficient (APNKO) mice underwent saline or aldosterone infusion and uninephrectomy and were fed 1% salt water for 4 wk. Blood pressure was increased in aldosterone-infused WT (132 +/- 2 vs. 109 +/- 3 mm Hg; P < 0.01) and further augmented in APNKO mice (140 +/- 3 mm Hg; P < 0.05 vs. aldosterone-infused WT). LVH was increased in aldosterone-infused WT vs. WT mice (LV/body weight ratio, 4.8 +/- 0.2 vs. 4.1 +/- 0.2 mg/g) and further increased in aldosterone-infused APNKO mice (LV/body weight ratio, 6.0 +/- 0.4 mg/g). Left ventricular ejection fraction was not decreased in either aldosterone-infused WT or APNKO hearts. Pulmonary congestion however was worse in APNKO mice (P < 0.01). The ratio of early ventricular filling over late ventricular filling (E/A) and the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e'), measures of diastolic function, were increased in aldosterone-infused WT hearts and further increased in APNKO hearts (P < 0.05 for both). Renal function and cardiac fibrosis were no different between both aldosterone-infused groups. Aldosterone increased matrix metalloproteinase-2 expression in WT hearts (P < 0.05 vs. WT and P < 0.01 vs. APNKO). Myocardial atrial natriuretic peptide, interferon-gamma, and TNF-alpha expression were increased in aldosterone-infused WT hearts. Expression of these proteins was further increased in aldosterone-infused APNKO hearts. Therefore, hypoadiponectinemia in hypertension-induced diastolic HF exacerbates LVH, diastolic dysfunction, and diastolic HF. Whether or not adiponectin replacement prevents the progression to diastolic HF will warrant further study.

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Figures

Figure 1

Figure 1

Adiponectin levels in aldosterone- or saline-infused WT mice. A, Plasma adiponectin (APN) levels are decreased in WT-aldosterone mice at the end of 4 wk; B and C, distribution of the three oligomeric forms of adiponectin in plasma as determined by Western blot analysis, with 1 μl plasma was loaded in each lane; C, representative Western blot; D, at 4 wk, aldosterone levels were no different between WT-aldosterone and APNKO-aldosterone mice; n = 5–10 per group. ND, Not detected.

Figure 2

Figure 2

In vivo transthoracic echocardiography measurements and ANP expression in WT and APNKO mice 4 wk after surgery. A, LVEDD; B, LVESD; C, ejection fraction (EF); D, total wall thickness (TWT). *, P < 0.05 vs. WT-saline; †, P < 0.01 vs. APNKO-saline; n = 5–10 per group. E, ANP protein expression was increased in WT-aldosterone hearts (‡, P < 0.01 vs. WT-saline) and in APNKO-aldosterone (§, P < 0.05 vs. APNKO-saline). F, Representative immunoblot of myocardial ANP expression; n = 5–10 per group. Data are mean ±

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. NS, Not significant.

Figure 3

Figure 3

Cardiac fibrosis and renal function in aldosterone-infused APNKO and WT mice. A, Qualitatively, there is more fibrosis in both WT- and APNKO-aldosterone hearts vs. WT- and APNKO-saline hearts. B, Percentage of myocardial fibrosis is increased in both WT- and APNKO-aldosterone hearts. **, P < 0.001; †, P < 0.01 vs. respective saline for both. There was no difference in fibrosis between WT and APNKO-aldosterone hearts. Data are mean ±

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and reflects 10 measurements from three sections each for WT and APNKO (n = 3) hearts. C–E, TGF-β (C), type I collagen (D), and type I collagen (E) expression was not different between aldosterone-infused WT and APNKO hearts. F, Four weeks after uninephrectomy and aldosterone/saline infusion, histology of the remaining kidney in WT and APNKO were analyzed. Note the lack of differences in the glomeruli and tubules between WT-aldosterone and APNKO-aldosterone mice. G and H, Mean values of glomerular cross-sectional area (G) and the number of intraglomerular cells (H) were quantitatively measured. ‡, P < 0.01 vs. WT-saline; †, P < 0.01 vs. APNKO saline. I, Urinary excretion of albumin (Alb)/creatinine (Cr) (milligrams per gram Cr) was increased in both groups of aldosterone-infused mice. There was no difference between WT-aldosterone and APNKO-aldosterone mice. ‡, P < 0.01 vs. WT-saline; †, P < 0.01 vs. APNKO saline; n = 5 per group. NS, Not significant.

Figure 4

Figure 4

Myocardial MMP, TIMP, and cytokine protein expression in WT and APNKO aldosterone-infused mice. A, MMP-2 expression was increased in WT-aldosterone hearts (‡, P < 0.01) and also increased in APNKO-aldosterone (§, P < 0.05) vs. respective controls. B, TIMP-2 expression was nonsignificantly increased in WT-aldosterone hearts and not expressed in APNKO-aldosterone vs. respective controls. C, MMP-9 expression was increased in WT-aldosterone hearts (**, P < 0.001) and in APNKO-aldosterone hearts (#, P < 0.001) vs. respective controls. D, TIMP-1 expression was nonsignificantly increased in WT-aldosterone and APNKO-aldosterone hearts vs. respective controls. E, TNF-α protein expression was increased in WT-aldosterone (**, P < 0.001) and in APNKO-aldosterone hearts (†, P < 0.01) vs. respective controls. There were no differences between aldosterone-infused hearts. F, IFN-γ protein expression was increased in WT-aldosterone (*, P < 0.05) and APNKO-aldosterone (†, P < 0.01) vs. respective controls. Additionally, aldosterone significantly increased IFN-γ expression in APNKO hearts vs. WT-aldosterone); data are mean ±

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; n = 5–10 per group. NS, Not significant.

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