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Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl-4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. Methods and Results Mice with Egln1Tie2Cre (Tie2-Cre-mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. Conclusions The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF-2α-dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

Transmembrane protein 100 (TMEM100) is a crucial factor in the development and maintenance of the vascular system. The protein is involved in several processes such as angiogenesis, vascular morphogenesis, and integrity. Furthermore, TMEM100 is a downstream target of the BMP9/10 and BMPR2/ALK1 signaling pathways, which are key regulators of vascular development. Our recent studies have shown that TMEM100 is a lung endothelium enriched gene and plays a significant role in lung vascular repair and regeneration. The importance of TMEM100 in endothelial cells' regeneration was demonstrated when Tmem100 was specifically deleted in endothelial cells, causing an impairment in their regenerative ability. However, the role of TMEM100 in various conditions and diseases is still largely unknown, making it an interesting area of research. This review summarizes the current knowledge of TMEM100, including its expression pattern, function, molecular signaling, and clinical implications, which could be valuable in the development of novel therapies for the treatment of cardiovascular and pulmonary diseases. [ABSTRACT FROM AUTHOR]

BMP signaling deficiency is evident in the lungs of patients with pulmonary arterial hypertension. We demonstrated that PHD2 deficiency suppresses BMP signaling in the lung endothelial cells, suggesting the novel mechanisms of dysregulated BMP signaling in the development of pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

A unique serpin, kallistatin, displays vasodilatory, antiangiogenic, anti-inflammatory, and antioxidant activity. Difficulty and low efficacy of obtaining recombinant kallistatin limit the wide investigation of its biological and pathological function. The present study employed a codon optimization algorithm to redesign the kallistatin gene and achieved a high yield of recombinant kallistatin protein. The kallistatin codons were redesigned for a more suitable Escherichia coli host without altering amino acids. Base composition and GC% content were compared between synthetic optimized kallistatin (opti-kallistatin) and wild-type kallistatin (wt-kallistatin). Both opti-kallistatin and wt-kallistatin were purified using Ni-NTA His-binding resins through fast protein liquid chromatography (FPLC). The identity and purity of kallistatin were confirmed by Coomassie blue staining, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and Western blot analysis. The output of opti-kallistatin protein was ∼2-fold increase (2.09 ± 0.23 mg/L) compared to wt-kallistatin (1.05 ± 0.2 mg/L). These results suggest that more common codon optimization in the E. coli host significantly increases the yield of heterologous human protein yields. This approach will remarkably facilitate the further investigation of kallistatin in vitro and in vivo. [ABSTRACT FROM PUBLISHER]