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Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz -deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy. • Yap1/Taz deletion in ECs causes vascular dysfunction and lethality in male mice. • IR activates Yap1/Taz in EC to maintain vascular integrity and mouse survival. • Yap1/Taz deletion disrupts gene expression of tight junction components. [ABSTRACT FROM AUTHOR]

Highlights: [•] Smooth muscle cells of ATGL-deficient mice (ATGL−/−mSMC) were isolated from aorta. [•] ATGL−/−mSMC showed spontaneous lipid accumulation and distinct phenotypic characters. [•] Adenoviral expression of wild type ATGL reduced lipid accumulation in ATGL−/−mSMC. [•] Adenoviral expression of wild type ATGL corrected distinct phenotype of ATGL−/−mSMC. [•] Phenotypic plasticity of lipid accumulated SMC may be potential therapeutic target. [ABSTRACT FROM AUTHOR]

Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare and newly identified disease among patients requiring cardiac transplantation. TGCV is characterized by cardiomyocyte steatosis and triglyceride (TG)-deposit atherosclerosis, resulting from the abnormal intracellular metabolism of TG. TGCV is classified into primary and idiopathic types. Primary TGCV carries ultra-rare genetic mutations in the adipose triglyceride lipase (ATGL), a rate-liming enzyme that hydrolyzes intracellular TG in adipose and non-adipose tissues. Idiopathic TGCV, first identified among autopsied individuals with diabetes mellitus (DM) with severe heart diseases, shows no ATGL mutations and its causes and underlying mechanisms are still unknown. TGCV is difficult to diagnose in daily clinics, thereby demanding feasible diagnostic procedures. We aimed to develop an assay to measure ATGL activity using peripheral leucocytes. Human his6-ATGL was expressed in COS1 cells, purified to homogeneity, and used to raise a polyclonal antibody neutralizing TG-hydrolyzing activity of ATGL. We developed a selective immunoinactivation assay (SIIA) for the quantitation of ATGL activity in cell lysates of leucocytes by the antibody neutralizing ATGL activities. ATGL activity was measured in 13 idiopathic TGCV patients, with two patients with primary TGCV as the negative control. Healthy (non-DM) and DM controls without heart diseases were also subjected. The developed SIIA assay revealed significant reduction in ATGL activity in leucocytes from patients with idiopathic TGCV who did not carry ATGL mutations as compared with non-DM and DM controls. Thus, ATGL in leucocytes may be an important biomarker for the diagnosis of TGCV and our assay may provide insights into pathophysiology and elucidate the underlying mechanism of TGCV and related disorders. [ABSTRACT FROM AUTHOR]

Highlights: [•] Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare severe heart disease. [•] PPARγ is up-regulated in myocardium in patients with TGCV. [•] Possible vicious cycle for fatty acid may be involved in pathophysiology of TGCV. [Copyright &y& Elsevier]