ARGININE METABOLISM AND ARTERIAL COMPLIANCE IN HYPERTENSION: THE EFFECT OF NEBIVOLOL THERAPY

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to liver cancer because it was detected at an advanced stages in patients with liver dysfunction, making HCC a lethal cancer. Accordingly, we aim to new targets for HCC drug discovery using HCC tumor spheroids. Methods Our comparative proteomic analysis of HCC cells grown in culture as monolayers (2D) and spheroids (3D) revealed that argininosuccinate synthase 1 (ASS1) expression was higher in 3D cells than in 2D cells due to upregulated endoplasmic reticulum (ER) stress responses. We investigated the clinical value of ASS1 in Korean patients with HCC. The mechanism underlying ASS1-mediated tumor suppression was investigated in HCC spheroids. ASS1-mediated improvement of chemotherapy efficiency was observed using high content screening in an HCC xenograft mouse model. Results Studies of tumor tissue from Korean HCC patients showed that, although ASS1 expression was low in most samples, high levels of ASS1 were associated with favorable overall survival of patients. Here, we found that bidirectional interactions between ASS1 ER stress responses in HCC-derived multicellular tumor spheroids can limit HCC progression. ASS1 overexpression effectively inhibited tumor growth and enhanced the efficacy of in vitro and in vivo anti-HCC combination chemotherapy via activation of the PERK/eIF2α/ATF4/CHOP axis, but was not dependent on the status of p53 and arginine metabolism. Conclusions These results demonstrate the critical functional roles for the arginine metabolism–independent tumor suppressor activity of ASS1 in HCC and suggest that upregulating ASS1 in these tumors is a potential strategy in HCC cells with low ASS1 expression.

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Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00128.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. H259-H264 ◽

Cited By ~ 45

Author(s):

Robert V. MacKenzie Ross ◽

Mark R. Toshner ◽

Elaine Soon ◽

Robert Naeije ◽

Joanna Pepke-Zaba

Keyword(s):

Pulmonary Hypertension ◽

Time Constant ◽

Pulmonary Circulation ◽

Wave Reflection ◽

Arterial Compliance ◽

Chronic Thromboembolic Pulmonary Hypertension ◽

Left Heart Failure ◽

Thromboembolic Pulmonary Hypertension ◽

Pulmonary Arterial ◽

Rc Time Constant

This study analyzed the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance ( Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC time constant), or PVR × Ca, remains unaltered in various forms and severities of pulmonary hypertension, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of the decreased RC time constant. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH ( n = 78), proximal CTEPH ( n = 91) before (pre) and after (post) pulmonary endarterectomy (PEA), and distal CTEPH ( n = 53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (PAP) of ≤25 mmHg. Outcome measures were the RC time constant, PVR, Ca, and relationship between systolic and mean PAPs. The RC time constant for pre-PEA CTEPH was 0.49 ± 0.11 s compared with post-PEA-CTEPH (0.37 ± 0.11 s, P < 0.0001), IPAH (0.63 ± 0.14 s, P < 0.001), and distal CTEPH (0.55 ± 0.12 s, P < 0.05). A shorter RC time constant was associated with a disproportionate decrease in systolic PAP with respect to mean PAP. We concluded that the pulmonary RC time constant is decreased in proximal CTEPH compared with IPAH, pre- and post-PEA, which may be explained by increased wave reflection but also, importantly, by persistent structural changes after the removal of proximal obstructions. A reduced RC time constant in CTEPH is in accord with a wider pulse pressure and hence greater right ventricular work for a given mean PAP.

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