Krüppel-like factor 5 (KLF5) is a zinc-finger transcription factor known to play a pivotal role in the pathogenesis of cardiovascular disease. Here, we show that neonatal heterozygous KLF5 knockout mice exhibit a marked deficiency in white adipose tissue development, suggesting that KLF5 is also required for adipogenesis. In 3T3-L1 preadipocytes, KLF5 expression was induced at an early stage of differentiation, and this was followed by expression of PPARgamma2. Constitutive overexpression of dominant-negative KLF5 inhibited adipocyte differentiation, whereas overexpression of wild-type KLF5 induced differentiation even without hormonal stimulation. Moreover, embryonic fibroblasts obtained from KLF5+/- mice showed much attenuated adipocyte differentiation, confirming the key role played by KLF5 in adipocyte differentiation. KLF5 expression is induced by C/EBPbeta and delta. KLF5, in turn, acts in concert with C/EBPbeta/delta to activate the PPARgamma2 promoter. This study establishes KLF5 as a key component of the transcription factor network controlling adipocyte differentiation.
Alteration in the differentiated state of smooth muscle cells (SMCs) is known to be integral to vascular development and the pathogenesis of vascular disease. However, it is still largely unknown how environmental cues translate into transcriptional control of SMC genes. We found that deltaEF1 is upregulated during SMC differentiation and selectively transactivates the promoters of SMC differentiation marker genes, SM alpha-actin and SM myosin heavy chain (SM-MHC). DeltaEF1 physically interacts with SRF and Smad3, resulting in a synergistic activation of SM alpha-actin promoter. Chromatin immunoprecipitation assays and knockdown experiments showed that deltaEF1 is involved in the control of the SMC differentiation programs induced by TGF-beta signaling. Overexpression of deltaEF1 inhibited neointima formation and promoted SMC differentiation, whereas heterozygous deltaEF1 knockout mice exhibited exaggerated neointima formation. It thus appears deltaEF1 mediates SMC differentiation via interaction with SRF and Smad3 during development and in vascular disease.
Abstract-Modulation of smooth muscle cell (SMC) phenotype plays a central role in neointima formation. We recently demonstrated that Am80, a synthetic retinoic acid receptor ␣-specific agonist, inhibits the activity of the transcription factor KLF5, which is essential for neointima formation after vascular injury. In the present study, we aimed to further analyze the mechanism by which Am80 inhibits KLF5 and the effects of inhibiting KLF5 on SMCs and vascular lesion formation, as well as to evaluate potential of Am80 for use in the prevention of in-stent neointima formation. We found that Am80 inhibited both the expression and transcriptional function of KLF5. Of particular interest was our finding that KLF5 forms a transcriptionally active complex with unliganded RAR/RXR heterodimer on the PDGF-A promoter; Am80 disrupts this complex, thereby inhibiting KLF5-dependent transcriptional activation. Knocking down KLF5 using small interfering RNA suppressed serum-induced downregulation of SMC differentiation marker gene expression in cultured SMCs, and haploinsufficiency of KLF5 in mice attenuated phenotypic modulation of SMCs after vascular injury, indicating that KLF5 plays a key role in the control of SMC phenotype. Am80 augmented expression of the SMC differentiation marker genes in culture and within the vessel walls, and oral administration of Am80 significantly inhibited in-stent neointima formation in a rabbit stent-placement model. Taken together, these results demonstrate that KLF5 plays an important role in the control of SMC phenotype after vascular injury and suggest the feasibility of using Am80, delivered systemically and/or with a drug eluting stent, to prevent in-stent neointima formation. (Circ Res. 2005;97:1132-1141.)Key Words: stent Ⅲ smooth muscle Ⅲ restenosis Ⅲ retinoid Ⅲ phenotypic modulation T he neointima that forms after percutaneous coronary intervention (PCI) is mainly composed of smooth muscle cells (SMCs) and the extracellular matrix they produce. 1 In response to external stresses such as mechanochemical stress, the effects of various humoral factors, and direct interaction with inflammatory cells, SMCs undergo phenotypic modulation. These phenotypically modulated SMCs proliferate, migrate, and produce various paracrine factors, extracellular matrix, and matrix proteases, thereby promoting the remodeling of the vascular wall. 2,3 Consequently, SMCs are considered to be one of the most important targets of therapies aimed at preventing restenosis.We recently showed that the Krüppel-like transcription factor KLF5 mediates stress-induced vascular remodeling, and that haploinsufficiency of KLF5 in KLF5 ϩ/Ϫ mice much reduces neointima formation in vascular injury models. 4 Moreover, we identified a novel synthetic retinoid, Am80, to be a potent inhibitor of KLF5. 4 Am80 is a retinoic acid receptor (RAR) ␣-specific agonist that has been safely used to treat acute promyelocytic leukemia. As expected from its in vitro inhibitory effects on KLF5, Am80 inhibited neointima formation in a mous...
Immunoglobulin G4 (IgG4)-related systemic disease was first recognized as a clinicopathological entity about 10 years ago, and since then, it has attracted growing attention. It is an autoimmune disease which affects multiple organs including the pancreas, bile duct, salivary glands and retroperitoneum. Further, it was recently reported that it can be manifested as periarteritis, often as inflammatory abdominal aortic aneurysm. We describe the case of a 75-year-old man with autoimmune pancreatitis and parotitis who presented with angina. The serum concentration of IgG4 was significantly increased at 2,510 mg/dl. Coronary angiography showed multiple stenotic lesions and pronounced dilatation of the right coronary artery. Cardiac computed tomography disclosed increased wall thickness of the coronary arteries and focal tumorous lesions surrounding the right coronary artery. Treatment with steroids proved only marginally effective and he underwent surgical resection of the aneurysm and coronary artery bypass grafting. The diagnosis of IgG4-related systemic disease was confirmed by histological examination of the resected mass, which showed a massive infiltration of IgG4-positive plasma cells. This case emphasizes the importance of considering the diagnosis in any patient with abnormally increased wall thickness or ectatic lesions in the coronary arteries.
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