Kruppel-like factor 15 is critical for vascular inflammation

Abstract

Activation of cells intrinsic to the vessel wall is central to the initiation and progression of vascular inflammation. As the dominant cellular constituent of the vessel wall, vascular smooth muscle cells (VSMCs) and their functions are critical determinants of vascular disease. While factors that regulate VSMC proliferation and migration have been identified, the endogenous regulators of VSMC proinflammatory activation remain incompletely defined. The Kruppel-like family of transcription factors (KLFs) are important regulators of inflammation. In this study, we identified Kruppel-like factor 15 (KLF15) as an essential regulator of VSMC proinflammatory activation. KLF15 levels were markedly reduced in human atherosclerotic tissues. Mice with systemic and smooth muscle-specific deficiency of KLF15 exhibited an aggressive inflammatory vasculopathy in two distinct models of vascular disease: orthotopic carotid artery transplantation and diet-induced atherosclerosis. We demonstrated that KLF15 alters the acetylation status and activity of the proinflammatory factor NF-κB through direct interaction with the histone acetyltransferase p300. These studies identify a previously unrecognized KLF15-dependent pathway that regulates VSMC proinflammatory activation.

KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria

“…Recent reports have shown that KLF4 is implicated in vascular (32,33) and cardiac diseases (34), so our findings suggest the possibility that a reduction in KLF4 expression in multiple tissues may provide a common mechanism linking cardiovascular and renal diseases.…”

Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15

“…In particular, KLF15 has a wide matrix sequence highly overlapping the ZF6-cis sequence (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.96560DS1) and is expressed throughout the retina but not in photoreceptors (17) and thus can be excluded from having a regulatory function in these cells. In addition, although KLF15 exerts a wide range of regulatory functions in different organs and in system homeostasis (18)(19)(20), the mouse knockout does not exhibit prominent phenotypes (21). Before proceeding with KLF15 as a candidate for somatic ectopic expression, we confirmed that KLF15 is not expressed in terminally differentiated rod photoreceptors using immunofluorescence analysis in mouse, porcine, and human retina ( Figure 1B and Supplemental Figure 1).…”

Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

“…Recent studies have shown the importance of KLF15 in modulating gluconeogenesis, amino acid degradation, and urea cycle (26)(27)(28). Moreover, KLF15 regulates infl ammation by altering the acetylation status and activity of NF-B through direct interaction with p300 ( 45 ). Thus, the increased hepatic infl ammation we observed in the FMO3 ASO-treated mice might have been caused by impaired PPAR ␣ and KLF15 activities.…”