Abstract 313: KLF5 Plays an Important Role in Endoplasmic Reticulum Stress Response in both Cardiovascular and Metabolic System
We have previously shown that the transcription factor KLF5 plays an important role in cardiovascular diseases. KLF5 heterozygous knockout (KLF5+/−) mice exhibited much less neointima formation in vascular injury models and less severe cardiac hypertrophy and fibrosis in the angiotensin II-loading model. We have also found that KLF5 is expressed in metabolic tissues, such as adipose tissue, pancreatic β-cell, and skeletal muscle. When KLF5+/− mice were fed with high-fat diet, they were protected from metabolic syndrome. These findings demonstrate that KLF5 plays important roles in stress response in both cardiovascular and metabolic systems. To better understand how KLF5 responds to metabolic and inflammatory stress, we analyzed signaling pathways that activate KLF5. One such pathway was the unfolded protein response (UPR). Indeed, in KLF5+/− mice fed with high-fat diet exhibited much less severe pancreatic islets remodeling, in which endoplasmic reticulum (ER) stress and UPR have been shown to play an essential role. To further analyze KLF5’s role in ER stress responses, we treated mouse MIN6 pancreatic β cells with palmitate as a model of lipotoxicity. Palmitate induced ER stress markers, CHOP, Bip and phosphor-eIF2α. The increases in ER stress markers were accompanied by induction of KLF5, while insulin expression was decreased. When ER stress was attenuated by 4-phenylbutyrate and tauroursodeoxycholate, the induction of KLF5 and the down regulation of insulin expression were significantly inhibited. When the KLF5 was knocked down with siRNA, the down regulation of insulin mRNA expression in response to palmitate was suppressed. These results demonstrate that KLF5 is a downstream effecter protein of ER stress in β-cells and is involved in insulin expression. We then analyzed it in the cardiovascular system. We found that KLF5 was also induced by ER stress in smooth muscle cells (SMCs). Moreover, interleukin-1, which is known to induce inflammatory genes in SMCs, activated KLF5 via ER stress. Results of the present study suggest that KLF5 responds to ER stress in both cardiovascular and metabolic systems and that this signaling pathway plays important roles in pathogenesis and progression of metabolic syndrome as well as cardiovascular diseases.