Cardiomyocyte p65 Nuclear Factor-κB Is Necessary for Compensatory Adaptation to Pressure Overload

Abstract

Background Nuclear factor kappa B (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 pharmacologic inhibition of NF-κB at the time of acute pressure-overload accelerates the progression of left ventricular hypertrophy (LVH) 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 pathologic LVH through NF-κB related pathways. Methods and Results Transgenic mice (KO) were generated with cardiomyocyte (CMC)-specific deletion of the p65 subunit of NF-κB. Mice underwent transverse aortic constriction and serially followed with echocardiography for 6 weeks. CMC p65 NF-κB deletion promoted maladaptive LVH and accelerated progression towards heart failure, as measured by ejection fraction, LV mass, and lung congestion. Transgenic mice had higher levels of fibrosis and periostin expression. Whole-field digital microscopy revealed increased capillary domain areas in KO mice while concurrently demonstrating decreased microvessel density. This observation was associated with decreased expression of hypoxia-inducible factor 1α (HIF-1α). Conclusions Rather than developing compensatory LVH, pressure overload in CMC NF-κB deficient mice resulted in functional deterioration that was associated with increased fibrosis, decreased HIF 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.

Overexpression of lncRNA ANRIL up-regulates VEGF expression and promotes angiogenesis of diabetes mellitus combined with cerebral infarction by activating NF-κB signaling pathway in a rat model

“…Choudhuri et al verified in their study the relationship between NF-κB pathway activation and downstream up-regulation of VEGF in diabetic retinopathy (DR), a microvascular complication of DM, which was in accordance with our findings [21]. And the result was also supported by Polyakova who found that NF-κB inhibition resulted in functional deterioration that was associated with decreased MVD [22]. Furthermore, it was found out that knockout of lncRNA ANRIL combined with PDTC administration resulted in no change in FLK-1 expression but a decrease in FLT-1 expression.…”

Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload‐Induced Pathological Cardiac Hypertrophy

“…For instance, IKK/NF‐κB activation in cardiomyocytes caused inflammatory cardiomyopathy and heart failure, while inhibition of NF‐κB signaling by a nondegradable IκBα decreased cardiac hypertrophy and dysfunction induced by Ang II stimuli and pressure overload . Moreover, cardiac NF‐κB regulated angiogenesis and factors responsible for compensatory reaction to transverse aortic constriction–induced intracellular hypoxia, and cardiac‐specific deletion of p65 reduced the hypertrophic response after pressure overload stimulation . Consistently, in our present study, activation of NF‐κB signaling was observed in hypertrophic hearts, and SNIP1 overexpression suppressed the activation.…”

“…It is well known that NF‐κB signaling is indispensable for the regulation of various cardiovascular diseases, especially for cardiac hypertrophy, fibrosis, and ventricular remodeling . Nevertheless, the role of NF‐κB signaling in the regulation of cardiac hypertrophy remains controversial.…”

Periostin as a novel biomarker of cardiovascular disease: A systematic evidence landscape of preclinical and clinical studies

“…Periostin has been recognized as having important role in cardiac development and its pathophysiological mechanisms contributing to CVD. A sufficient evidence has suggested that the periostin plays an important role in coronary artery disease (CAD), hypertension valvular diseases (VHDs), and several cause of cardiac fibrosis …”