Hadi Javan1, Amanda M Szucsik1, Ling Li1, Christin L Schaaf1, Mohamed E Salama1, Craig H Selzman2. 1. From the Division of Cardiothoracic Surgery, Department of Surgery and Molecular Medicine (H.J., A.M.S., L.L., C.L.S., C.H.S.) and Department of Pathology, ARUP Institute for Research and Development (M.E.S.), University of Utah, Salt Lake City. 2. From the Division of Cardiothoracic Surgery, Department of Surgery and Molecular Medicine (H.J., A.M.S., L.L., C.L.S., C.H.S.) and Department of Pathology, ARUP Institute for Research and Development (M.E.S.), University of Utah, Salt Lake City. craig.selzman@hsc.utah.edu.
Abstract
BACKGROUND: 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 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-κB-related pathways. METHODS AND RESULTS: Transgenic mice were generated with cardiomyocyte-specific deletion of the p65 subunit of NF-κB. Mice underwent transverse aortic constriction and serially followed up with echocardiography for 6 weeks. Cardiomyocyte p65 NF-κB 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 1α. CONCLUSIONS: Rather than developing compensatory left ventricular hypertrophy, pressure overload in cardiomyocyte NF-κB-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-κB, and its regulation of hypoxic stress, as an important factor determining the path between adaptive hypertrophy and maladaptive heart failure.
BACKGROUND: 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 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-κB-related pathways. METHODS AND RESULTS:Transgenic mice were generated with cardiomyocyte-specific deletion of the p65 subunit of NF-κB. Mice underwent transverse aortic constriction and serially followed up with echocardiography for 6 weeks. Cardiomyocyte p65 NF-κB 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 1α. CONCLUSIONS: Rather than developing compensatory left ventricular hypertrophy, pressure overload in cardiomyocyte NF-κB-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-κB, and its regulation of hypoxic stress, as an important factor determining the path between adaptive hypertrophy and maladaptive heart failure.
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