Cardiothoracic
Inhibitory kappa-B kinase-β inhibition prevents adaptive left ventricular hypertrophy

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Abstract

Background

Most cardiovascular studies have implicated the central transcription factor nuclear factor kappa-B (NF-κB) as 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. Pressure overload, left ventricular hypertrophy (LVH), and heart failure represent a spectrum of disease that has both adaptive and maladaptive components. In contrast to its known effects related to myocardial ischemia–reperfusion, we hypothesized that NF-κB is necessary for the compensatory phase of cardiac remodeling.

Methods

C57BL6 mice underwent minimally invasive transverse aortic constriction with or without inhibition of the proximal NF-κB kinase, inhibitory kappa-B kinase-β. Isolated cardiomyocytes were cultured. Transthoracic echocardiography was performed on all mice.

Results

Inhibitory kappa-B kinase-β inhibition successfully decreased cardiomyocyte expression of phosphorylated p65 NF-κB and decreased expression of hypertrophic markers with stimulation in vitro. Three weeks after transverse aortic constriction, the mice treated with inhibitory kappa-B kinase-β inhibition more aggressively developed LVH, as measured by heart weight/body weight ratio, left ventricular mass, and wall thickness. These mice also demonstrated a functional decline, as measured by decreased fractional shortening and ejection fraction. These findings were associated with decreased protein expression of p65 NF-κB.

Conclusions

Although short-term pressure-overload results in compensatory LVH with normal cardiac function, NF-κB inhibition resulted in increased LVH that was associated with functional deterioration. These observations suggest that NF-κB is an important part of the adaptive phase of LVH, and its inhibition detrimentally affects cardiac remodeling.

Introduction

Nuclear factor kappa-B (NF-κB) is a well-known pluripotent transcription factor involved in the inflammatory and immune response [1], [2]. Most studies within the cardiovascular literature have focused on the undesirable aspects of NF-κB–driven transcriptional events. Various methods of inhibiting the NF-κB signaling pathways have been used to attenuate an undesirable response to injury [3], [4], [5], [6]. Imbedded within these reports is the concept that NF-κB is responsible for creating a “bad” phenotype (i.e., an injured heart). However, this pattern overlooks that fact that NF-κB is a vital part of our innate immunity and promotes survival signals. Some evidence has suggested that NF-κB promotes cardioprotection in models of ischemic preconditioning and coronary ligation [2], [7]. As such, understanding the adaptive and maladaptive balance of NF-κB activation remains largely unanswered [8].

Whether NF-κ promotes survival or death pathways is, in part, related to the environment and stimulus to which a cell or tissue is exposed. As opposed to the very noxious stimuli associated with acute ischemia–reperfusion injury, other relevant cardiovascular events are less dramatic, such as those associated with hypertension, valvular disease, and heart failure. We have developed a murine model of pressure overload that allows us to evaluate the development of compensatory, physiologic left ventricular hypertrophy (LVH), and its eventual, maladaptive progression to heart failure [9]. By removing a constricting band on the thoracic aorta, we can also assess the physiologic and molecular aspects of myocardial recovery [10]. Within this model system, we have also shown that various components of NF-κB signaling are activated in both the development and the regression of heart failure [11]. Within the paradigm of “good” versus “bad” NF-κB, we hypothesized that NF-κB is necessary for the development of compensated, adaptive hypertrophy. The logical follow-up would be that a molecular switch must occur that transitions such that excessive NF-κB stimulation actually becomes detrimental. The present study evaluated the former hypothesis by examining the influence of proximal NF-κB kinase blockade on mice subjected to pressure overload.

Section snippets

Surgical model

In accordance with an institutionally approved Institutional Animal Care and Use Committee protocol, minimally invasive transverse arch banding and debanding were performed in 10-week-old C57BL6 male mice (Charles River Laboratories, Wilmington, MA), as previously described [9]. In brief, the mice were anesthetized using inhaled isoflurane by way of a face mask. A midline neck incision was used to approach the anterior mediastinum. The transverse arch was identified, and a constrictive band was

Results

The best characterized signaling pathway, or canonical pathway, for NF-κB activation involves phosphorylation of the β-subunit of the proximal IKK complex (IKK-β), thereby allowing for subsequent phosphorylation and degradation of the inhibitory kappa-B alpha brake on translocation of the active p65 NF-κB subunit into the nucleus [3]. To validate our IKK-β inhibitor (Bay) within this model system, we tested the effect of Bay on isolated neonatal rat cardiomyocytes (Fig. 1). Both leukemia

Discussion

Pressure overload induced by transverse aortic constriction is a well-known model for promoting LVH. The law of LaPlace demands that as wall stress increases with enhanced afterload, the heart will increase its thickness. With ongoing overload (longer than 4 wk), the ventricle begins to dilate and enters a maladaptive phase, including the development of heart failure [11], [14]. In the present study, we have demonstrated that proximal kinase blockade of NF-κB during acute pressure overload

Conclusions

We have demonstrated that NF-κB is an important part of the normal response to pressure overload. Within the realm of innate immunity, it makes sense, at some level, that NF-κB is necessary for adaptive LVH [20]. That said, reconciling when NF-κB is acting “good” versus “bad” remains a challenge.

Acknowledgments

This work was funded in part by National Institutes of Health grant R01HL089592 (to C. H. Selzman) and the American College of Surgeons (to C. H. Selzman). We thank Mauricio Rojas, MD for his technical support. The authors have no disclosures.

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