Yasuyuki Onai

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 γ (IFN-γ) and tumor necrosis factor α 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-γ stimulation. Sensitized splenocytes increased SMC proliferation, and anti–PD-L1 mAb in combination with IFN-γ 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.

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 β-1 (TGF-β1), 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-β1 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.