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 (>4 weeks), the ventricle begins to dilate and enters a maladaptive phase including the development of heart failure [11
]. In the present study, we demonstrate that proximal kinase blockade of NF-κB during acute pressure-overload results in the early development of decompensated LVH. As opposed to the preponderance of studies that suggest that NF-κB mediates myocardial injury (i.e. related to ischemia-reperfusion), this report adds to the evidence that NF-κB actually plays an important homeostatic role in cardiac physiology.
We have previously demonstrated that during the progression phase of TAC-induced LVH, a pattern of NF-κB-dependent survival genes are expressed [11
]. This led us to examine the effect of NF-κB blockade on the early physiologic changes associated with pressure overload. Others have recently demonstrated the significant role of NF-κB signaling with this model system by constructing cardiomyocyte-specific deletions of IKK-β and NEMO/IKKγ [15
]. Both of these proteins are part of the IKK complex and their conditional absence promoted an aggressive development of dilated cardiomyopathy mediated, in part, by dysregulation of the oxidant stress response. These transgenic studies are confounded by the propensity of the mouse hearts to naturally dilate as well as compensatory upregulation of other NF-κB related genes, potentially distorting the effects of induced stress (pressure-overload) that occurs to non-genetically manipulated animals. As such, we felt pharmacologic inhibition was an important element to decipher the role of NF-κB and compensatory LVH. Indeed, our IKK-β inhibitor, albeit not as potent as its transgenic ablation, successfully decreased adult mouse heart NF-κB activity both in vitro
and in vivo
Notwithstanding the ischemia-reperfusion studies – with the noxious stimulus of acutely interrupted blood supply to the heart - the current study using chronic pressure overload demonstrates disparate results to other models of LVH. In particular, we and others have shown that isoproterenol or angiotensin-II induced LVH is abrogated with NF-κB blockade [17
]. A number of factors likely are in play including the microenvironment as well as the intensity and chronicity of stimulus. For example, phosphorylation of the natural NF-κB upstream brake, IκBα, can occur via serine and tyrosine phosphorylation pathways that are differentially activated depending on the pathophysiologic situation [19
We recognize that more work will be necessary to determine the mechanism by which NF-κB favorably promotes adaptive LVH. Putative targets include its transcriptional influence over fibrosis genes, myocardial structural proteins, and cell death programs. As previously mentioned, NF-κB is an important and beneficial component of the innate immunity, including the host’s response to infection and inflammation [20
]. These salubrious functions of NF-κB extend to its salubrious influence with regards to ischemic preconditioning and coronary ligation, perhaps through its interaction with heat shock proteins [2
]. Finally, although we have focused on the classic, canonical pathway of NF-κB stimulation, we must acknowledge that other non-canonical signals are active. Indeed, the p50-p105 axis has been shown to alternatively protect from and promote cardiac remodeling in ischemic models [21
]. These latter studies further support the previously mentioned issues related to the complexity of stimulus and environment.
Summarily, we demonstrate 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” will remain a challenge.