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Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart.

ABSTRACT: Diastolic dysfunction in the aging heart is a grave condition that challenges the life and lifestyle of a growing segment of our population. This report seeks to examine the role and interrelationship of inflammatory dysregulation in interstitial myocardial fibrosis and progressive diastolic dysfunction in aging mice. We studied a population of C57BL/6 mice that developed progressive diastolic dysfunction over 30 months of life. This progressive dysfunction was associated with increasing infiltration of CD45(+) fibroblasts of myeloid origin. In addition, increased rates of collagen expression as measured by cellular procollagen were apparent in the heart as a function of age. These cellular and functional changes were associated with progressive increases in mRNA for MCP-1 and IL-13, which correlated both temporally and quantitatively with changes in fibrosis and cellular procollagen levels. MCP-1 protein was also increased and found to be primarily in the venular endothelium. Protein assays also demonstrated elevation of IL-4 and IL-13 suggesting a shift to a Th2 phenotype in the aging heart. In vitro studies demonstrated that IL-13 markedly enhanced monocyte-fibroblast transformation. Our results indicate that immunoinflammatory dysregulation in the aging heart induces progressive MCP-1 production and an increased shift to a Th2 phenotype paralleled by an associated increase in myocardial interstitial fibrosis, cellular collagen synthesis, and increased numbers of CD45(+) myeloid-derived fibroblasts that contain procollagen. The temporal association and functional correlations suggest a causative relationship between age-dependent immunoinflammatory dysfunction, fibrosis and diastolic dysfunction.

SUBMITTER: Cieslik KA

PROVIDER: S-EPMC3019252 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart.

Cieslik Katarzyna A KA Taffet George E GE Carlson Signe S Hermosillo Jesus J Trial Joann J Entman Mark L ML

Journal of molecular and cellular cardiology 20101023 1

Diastolic dysfunction in the aging heart is a grave condition that challenges the life and lifestyle of a growing segment of our population. This report seeks to examine the role and interrelationship of inflammatory dysregulation in interstitial myocardial fibrosis and progressive diastolic dysfunction in aging mice. We studied a population of C57BL/6 mice that developed progressive diastolic dysfunction over 30 months of life. This progressive dysfunction was associated with increasing infiltr ...[more]

PMID: 20974150

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Project description: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.

Dataset Information

Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart.

Publications

Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart.

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