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

Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-γ agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-γ antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor ß-1 (TGF-ß1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-γ and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-γ and TIMP-1, and inhibition of TGF-ß1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-γ activation were suggested to be important in addition to suppression of Ang II activity.

Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction.

Several studies have demonstrated that NF-kappaB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-kappaB 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 IkappaB that acts via inhibition of IKK-beta, 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 < 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 end-diastolic area: vehicle, 74.13 +/- 3.57 mm(2); IMD-0354, 55.00 +/- 3.73 mm(2); P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 +/- 0.26; IMD-0354, 2.61 +/- 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 +/- 14.87 pg/ml; IMD-0354, 110.75 +/- 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-beta1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-kappaB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.

HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation.

OBJECTIVE: This study tested the hypothesis that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor affects T cell-mediated autoimmunity through inhibition of nuclear factor-kappaB (NFkappaB) and reduces the severity of experimental autoimmune myocarditis (EAM). METHODS: EAM was induced in Lewis rats by immunization with myosin. High-dose or low-dose fluvastatin or vehicle was administered orally for 3 weeks to rats with EAM. RESULTS: Fluvastatin reduced the pathophysiological severity of myocarditis. Fluvastatin inhibited expression of NFkappaB in the nuclei of myocardium in EAM. Fluvastatin reduced production of Th1-type cytokines, including interferon (IFN)-gamma and interleukin (IL)-2, and inhibited expression of inflammatory cytokine mRNAs in the myocardium. Infiltration of CD4-positive T cells into the myocardium and T cell proliferative responses were suppressed by fluvastatin. Plasma lipid levels did not differ between the groups. CONCLUSIONS: Fluvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines via inactivation of nuclear factor-kappaB, and this activity is independent of cholesterol reduction.

Blockade of the interaction between PD-1 and PD-L1 accelerates graft arterial disease in cardiac allografts.

BACKGROUND: Programmed death-1 (PD-1), a member of the CD28 family, has been identified. PD-1 is involved in the negative regulation of some immune responses. We evaluated the role of PD-ligand 1 (PD-L1) in graft arterial disease (GAD) of cardiac allografts and in smooth muscle cells (SMCs). METHODS AND RESULTS: C57BL/6 murine hearts were transplanted into B6.C-H2KhEg mice for examination of GAD. PD-L1 was expressed in SMCs of the thickened intima in the graft coronary arteries, and administration of anti-PD-L1 monoclonal antibody (mAb) enhanced the progression of GAD (luminal occlusion: 55+/-5.0% versus 9.8+/-4.3%, P<0.05). The expressions of interferon gamma (IFN-gamma) and tumor necrosis factor alpha of cardiac allografts were upregulated in response to anti-PD-L1 mAb treatment. In vitro, PD-L1 expression was induced in SMCs in response to IFN-gamma stimulation. Sensitized splenocytes increased SMC proliferation, and anti-PD-L1 mAb in combination with IFN-gamma stimulation increased this proliferation. CONCLUSIONS: The PD-L1 pathway regulates both the proliferation of SMCs and GAD. Thus, control of this interaction is a promising strategy for suppression of GAD.

Inhibition of IkappaB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury.

OBJECTIVE: Reperfusion injury is related closely to inflammatory reactions such as activation of inflammatory cells and expression of cytotoxic cytokines. We investigated the efficacy of IkappaB phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model. METHODS AND RESULTS: IMD-0354 inhibited phosphorylation of IkappaBalpha and nuclear translocation of nuclear factor-kappa B (NF-kappaB) induced by tumor necrosis factor-alpha (TNF-alpha) in cultured cardiomyocytes. TNF-alpha-induced production of interleukin-1beta and monocyte chemoattractant protein-1 from cultured cardiomyocytes was reduced significantly by IMD-0354. Transient left coronary artery occlusion (30 min) and reperfusion (24 h) were carried out in Sprague-Dawley rats. IMD-0354 (1, 5, 10 mg/kg) was injected intraperitoneally 5 min before the start of reperfusion. Treatment with IMD-0354 resulted in a significant dose-dependent reduction of the infarction area/area at risk ratio (vehicle, 47.0+/-3.4%; 10 mg/kg of IMD-0354, 19.4+/-4.0%; P<0.01) and the preservation of fractional shortening ratio (vehicle, 25.0+/-1.5%; 10 mg/kg of IMD-0354, 42.3+/-1.7%; P<0.01). Histological analysis showed that accumulation of polymorphonuclear neutrophils in the area at risk was decreased significantly. CONCLUSIONS: Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes.

Blockade of cell adhesion by a small molecule selectin antagonist attenuates myocardial ischemia/reperfusion injury.

Reperfusion injury is related closely to inflammatory reactions such as the activation and accumulation of neutrophils. We investigated the efficacy of a novel small molecule selectin antagonist (bimosiamose) in a rat model of transient left coronary artery occlusion (30 min) and reperfusion (24 h). Treatment with bimosiamose (25 mg/kg, intravenously at reperfusion) showed a significant reduction in infarction area/area at risk of approximately 41% compared to vehicle control (P=0.01) and preserved the left ventricular function. The accumulation of polymorphonuclear neutrophils at the site of area at risk was decreased significantly, accompanied by 78% reduction of the myeloperoxidase activity. Parallel-plate flow chamber analysis revealed that bimosiamose showed a significant inhibition in rolling (62%, P<0.001) and adhesion (38%, P<0.05) of HL-60 cells to activated human umbilical vein endothelial cells compared with vehicle control. This study demonstrates for the first time that bimosiamose, a novel small molecule selectin antagonist, attenuates significantly ischemia/reperfusion injury.