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Cardiomyocyte p65 nuclear factor-?B is necessary for compensatory adaptation to pressure overload.

ABSTRACT: Nuclear factor ?B (NF-?B) is often implicated in contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-?B competes with its important role in the normal host inflammatory and immune response. We have previously demonstrated that pharmacological inhibition of NF-?B at the time of acute pressure overload accelerates the progression of left ventricular hypertrophy to heart failure in mice. NF-?B regulates angiogenesis and other factors responsible for compensatory reaction to intracellular hypoxia. We hypothesized that impaired angiogenesis may be the trigger, not the result, of pathological left ventricular hypertrophy through NF-?B-related pathways.Transgenic mice were generated with cardiomyocyte-specific deletion of the p65 subunit of NF-?B. Mice underwent transverse aortic constriction and serially followed up with echocardiography for 6 weeks. Cardiomyocyte p65 NF-?B deletion promoted maladaptive left ventricular hypertrophy and accelerated progression toward heart failure as measured by ejection fraction, left ventricular mass, and lung congestion. Transgenic mice had higher levels of fibrosis and periostin expression. Whole-field digital microscopy revealed increased capillary domain areas in knockout mice while concurrently demonstrating decreased microvessel density. This observation was associated with decreased expression of hypoxia-inducible factor 1?.Rather than developing compensatory left ventricular hypertrophy, pressure overload in cardiomyocyte NF-?B-deficient mice resulted in functional deterioration that was associated with increased fibrosis, decreased hypoxia-inducible factor expression, and decreased microvessel density. These observations mechanistically implicate NF-?B, and its regulation of hypoxic stress, as an important factor determining the path between adaptive hypertrophy and maladaptive heart failure.

SUBMITTER: Javan H

PROVIDER: S-EPMC4303522 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Cardiomyocyte p65 nuclear factor-κB is necessary for compensatory adaptation to pressure overload.

Javan Hadi H Szucsik Amanda M AM Li Ling L Schaaf Christin L CL Salama Mohamed E ME Selzman Craig H CH

Circulation. Heart failure 20141205 1

<h4>Background</h4>Nuclear factor κB (NF-κB) is often implicated in contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. We have previously demonstrated that pharmacological inhibition of NF-κB at the time of acute pressure overload accelerates the progression of left ventricular hypertrophy to heart failure in mice. NF-κB regulates angiogenesis and other factors res ...[more]

PMID: 25480781

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Project description:BackgroundRecently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress.MethodsWe performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling.ResultsWe first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction.ConclusionsCollectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

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Cardiomyocyte p65 nuclear factor-?B is necessary for compensatory adaptation to pressure overload.

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Cardiomyocyte p65 nuclear factor-κB is necessary for compensatory adaptation to pressure overload.

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