Akap1 Regulates Vascular Function and Endothelial Cells Behavior

Abstract

MitoAKAPs (mitochondrial A kinase anchoring proteins), encoded by the gene, regulate multiple cellular processes governing mitochondrial homeostasis and cell viability. Although mitochondrial alterations have been associated to endothelial dysfunction, the role of mitoAKAPs in the vasculature is currently unknown. To test this, postischemic neovascularization, vascular function, and arterial blood pressure were analyzed in knockout mice ( ) and their wild-type (wt) littermates. Primary cultures of aortic endothelial cells (ECs) were also obtained from and wt mice, and ECs migration, proliferation, survival, and capillary-like network formation were analyzed under different experimental conditions. After femoral artery ligation, mice displayed impaired blood flow and functional recovery, reduced skeletal muscle capillary density, and Akt phosphorylation compared with wt mice. In ECs, a significant enhancement of hypoxia-induced mitophagy, mitochondrial dysfunction, reactive oxygen species production, and apoptosis were observed. Consistently, capillary-like network formation, migration, proliferation, and AKT phosphorylation were reduced in ECs. Alterations in ECs behavior were also confirmed in mice, which exhibited a selective reduction in acetylcholine-induced vasorelaxation in mesenteric arteries and a mild but significant increase in arterial blood pressure levels compared with wt. Finally, overexpression of a constitutively active Akt mutant restored vascular reactivity and ECs function in conditions. These results demonstrate the important role of mitoAKAPs in the modulation of multiple ECs functions in vivo and in vitro, suggesting that mitochondria-dependent regulation of ECs might represent a novel therapeutic approach in cardiovascular diseases characterized by endothelial dysfunction.

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

“…Loss of AKAP1 inactivates Akt signaling and increases apoptosis in cardiac dysfunction 62,63 . The Akt pathway controls the expression of apoptosis-related genes through transcription factors such as FoxO (FoxO1 and FoxO3a) 64,65 and Akt activation promotes cell survival by inhibiting the FoxO3a/Bim/Bax pathway 48,64,65 .…”

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

“…Loss of AKAP1 inactivates Akt signaling and increases apoptosis in cardiac dysfunction 57,58 . Akt pathway controls the expression of apoptosis-related gene through transcription factors such as FoxO (FoxO1 and FoxO3a) 59,60 and Akt activation promotes cell survival by inhibiting FoxO3a/Bim/Bax pathway 55,59,60 .…”

A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease

“…AKAP1 has also been studied in the regulation of vascular functions. The same group also reported alterations of endothelial cell behavior in AKAP1 KO mice as well as a mild increase in blood pressure [26].…”

“…The AKAP1 knockout mouse was generated by deletion of the first coding exon that includes the mitochondrial targeting sequence and the PKA binding site [22]. Even though the AKAP1 knockout mouse was generated over a decade ago [22], a recent flurry of publications has described the use of the AKAP1 gene deletion to tease out the function of AKAP1 in a variety of tissues [23][24][25][26][27][28]. As we begin to discuss the specific roles of AKAP1 in mitochondrial form and function, it is worth noting how the dynamic changes in mitochondrial morphology impact function.…”