Abstract 5275: Kruppel-Like Factor 15 Regulates the Cardiovascular Response to Angiotensin II
Background: Angiotensin II (A-II) causes pathologic remodeling of the heart and vasculature through gene-regulatory pathways that are incompletely understood. We and others have identified Kruppel-Like Factor 15 (KLF15) as a transcription factor that may exert beneficial effects in the cardiovascular system, however, its role in A-II signaling remains unknown. We hypothesize that KLF15 can modulate the deleterious effects of A-II on the heart and blood vessel.
Methods and Results: A-II downregulates KLF15 expression in heart and vascular tissues in vitro and in vivo. Mice with systemic KLF15 deficiency (male, age 10 wks) have baseline abnormalities of the heart (increased cardiac mass, LV thickness, fetal gene expression) and vasculature (thickened aortic media with elastin breakdown). In response to chronic A-II infusion (1.4 mg/kg/D x 14D), KLF15 KO mice develop severe degenerative changes in both the heart and vessel compared to wild-type controls. In the heart, KLF15 KO mice develop pronounced heart failure characterized by augmented cardiac mass, eccentric LV remodeling, profound LV systolic dysfunction, increased fibrosis, enhanced fetal gene expression and apoptotic cell loss. Dramatic degenerative changes also occur in the aorta of KLF15 KO mice including medial destruction with elastin degradation, outward remodeling with vessel dilation, augmented inflammatory gene expression, and foci of severe smooth muscle apoptosis. Mechanistically, there is exaggerated accumulation of p53 and its direct pro-apoptotic targets in the heart (Bax) and aorta (Bax, p21) of KLF15 KO mice. As p53-mediated degradation of HIF1α has been implicated in cardiac decompensation, we show that KLF15 KO hearts have decreased HIF1α levels and fail to mount an angiogenic response to A-II. Finally, we provide evidence that KLF15 can directly inhibit p53 protein accumulation in a proteasome-dependent manner.
Conclusion: KLF15 deficiency renders the cardiovascular system exquisitely sensitive to A-II stimulation and leads to degenerative remodeling of the heart and blood vessel with exaggerated p53 accumulation in these tissues. These findings suggest that manipulation of KLF15 function may provide novel approaches to inhibit the pathologic effects of A-II.