Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

Abstract

August 18, 2006; doi:10.1152/ajpheart.00549.2006.-Several studies have demonstrated that NF-B is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-B is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of I B that acts via inhibition of IKK-␤, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P Ͻ 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV enddiastolic area: vehicle, 74.13 Ϯ 3.57 mm 2 ; IMD-0354, 55.00 Ϯ 3.73 mm 2 ; P Ͻ 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 Ϯ 0.26; IMD-0354, 2.61 Ϯ 0.24; P Ͻ 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 Ϯ 14.87 pg/ml; IMD-0354, 110.75 Ϯ 6.41 pg/ml; P Ͻ 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-␤1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-B activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI. experimental heart failure; nuclear factor-b; matrix metalloproteinase; echocardiography MYOCARDIAL INFARCTION (MI) frequently leads to left ventricular (LV) dilatation and associated interstitial fibrosis in the noninfarcted myocardium. This adverse LV remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after MI (20). One of the recent conceptual advances in our understanding of the pathogenesis of LV remodeling is that this process is driven by the overexpression of various factors, including proinflammatory cytokines, angiotensin II, and norepinephrine, which have direct pathophysiological effects on cardiac myocytes, noncardiac myocytes, and the extracellular matrix (20). Although the expression of proinflammatory cytokines may be involved in wound healing after MI, it is believed that the overexpression of cytokines damages cardiac tissue and evokes excess deposition of fibrotic components, even in the noninfarcted myocardium.Several recent studies reported that nuclear factor-B (NF-B) is involved in the pathogenesis of heart failure (7, 35). Activation of NF-B induces activation of genetic programs that lead to transactivation of cytokines, chemokines, and matrix metalloproteinases (MMPs), promoting inflammatory and fibrotic responses that participate in the progre...

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

“…As such, cardiac-specific deletion of Capn4, via prevention of IB degradation and NF-B activation, inhibits inflamma- tory responses and blocks both autocrine and paracrine signalings induced by local proinflammatory cytokines from cardiomyocytes, leading to a reduction in myocardial remodeling and an improvement of myocardial function in the MI heart. Given the critical role of NF-B signaling in cardiac remodeling (25,43), IB degradation and consequent NF-B activation may represent an important mechanism for calpain-mediated remodeling after MI. It is worthwhile to mention that calpain from cardiac fibroblasts may also contribute to post-MI myocardial remodeling because our recent study has revealed an important role of calpain in proliferation of cardiac fibroblasts (30).…”

“…Degradation of IB frees NF-B dimmers and allows translocation of NF-B into the nucleus, where it can initiate transcription of target genes. Following MI, activation of NF-B contributes to maladaptive LV remodeling and functional deterioration by promoting inflammatory responses (25). Calpain activation has been demonstrated to induce IB degradation and NF-B activation (26,27).…”

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

“…Then the chest was closed, and the animals were allowed to recover in a warm, clean cage. 13 Rats that died within 24 h of the operation were excluded from this study.…”

“…As an index of LV diastolic function, the ratio of the peak velocity of the early (E) to late (A) filling waves was determined from Doppler images of mitral flow obtained in the apical four-chamber view, as described previously. 13 Each value was the average of measurements over three consecutive beats, and data were obtained by blinded observers.…”

Chlorogenic Acid Attenuates Ventricular Remodeling After Myocardial Infarction in Mice

“…Many studies have shown that macrophage related inflammatory responses are increased by myocardial necrosis. 2,3) These inflammatory responses lead to an increase in fibroblasts and increased collagen synthesis. [4][5][6][7] Chlorogenic acid (8-tetrahydroxycyclohexacarboxylic acid, 3-(3,4-dihydroxycinnamate, CGA) is a key component of coffee.…”