Objective: Hypoxia-induced pulmonary hypertension (HPH) increases lipid peroxidation with generation of toxic aldehydes that are metabolized by detoxifying enzymes, including ALDH2 (aldehyde dehydrogenase 2). However, the role of lipid peroxidation and ALDH2 in HPH pathogenesis remain undefined. Approach and Results: To determine the role of lipid peroxidation and ALDH2 in HPH, C57BL/6 mice, ALDH2 transgenic mice, and ALDH2 knockout (ALDH2 −/− ) mice were exposed to chronic hypoxia, and recombinant tissue-specific ALDH2 overexpression adeno-associated viruses were introduced into pulmonary arteries via tail vein injection for ALDH2 overexpression. Human pulmonary artery smooth muscle cells were used to elucidate underlying mechanisms in vitro. Chronic hypoxia promoted lipid peroxidation due to the excessive production of reactive oxygen species and increased expression of lipoxygenases in lung tissues. 4-hydroxynonenal but not malondialdehyde level was increased in hypoxic lung tissues which might reflect differences in detoxifying enzymes. ALDH2 overexpression attenuated the development of HPH, whereas ALDH2 knockout aggravated it. Specific overexpression of ALDH2 using AAV1 (adeno-associated virus)-ICAM (intercellular adhesion molecule) 2p-ALDH2 and AAV2-SM22αp (smooth muscle 22 alpha)-ALDH2 viral vectors in pulmonary artery smooth muscle cells, but not endothelial cells, prevented the development of HPH. Hypoxia or 4-hydroxynonenal increased stabilization of HIF (hypoxia-inducible factor)-1α, phosphorylation of Drp1 (dynamin-related protein 1) at serine 616, mitochondrial fission, and pulmonary artery smooth muscle cells proliferation, whereas ALDH2 activation suppressed the latter 3. Conclusions: Increased 4-hydroxynonenal level plays a critical role in the development of HPH. ALDH2 attenuates the development of HPH by regulating mitochondrial fission and smooth muscle cell proliferation suggesting ALDH2 as a potential new therapeutic target for pulmonary hypertension.

The heavy metal cadmium is a non-degradable pollutant. By screening the effects of a panel of metal ions on the phosphatase activity, we unexpectedly identified cadmium as a potent inhibitor of PPM1A and PPM1G. In contrast, low micromolar concentrations of cadmium did not inhibit PP1 or tyrosine phosphatases. Kinetic studies revealed that cadmium inhibits PPM phosphatases through the M1 metal ion binding site. In particular, the negative charged D441 in PPM1G specific recognized cadmium. Our results suggest that cadmium is likely a potent inhibitor of most PPM family members except for PHLPPs. Furthermore, we demonstrated that cadmium inhibits PPM1A-regulated MAPK signaling and PPM1G-regulated AKT signaling potently in vivo. Cadmium reversed PPM1A-induced cell cycle arrest and cadmium insensitive PPM1A mutant rescued cadmium induced cell death. Taken together, these findings provide a better understanding of the effects of the toxicity of cadmium in the contexts of human physiology and pathology.

Perihilar cholangiocarcinoma (PHCCA) is the most common type of cholangiocarcinoma with low resection rate and high morbidity. The study of PHCCA biomarkers made progresses slowly compared with intrahepatic cholangiocarcinoma because of surgical complexity and low possibility of radical surgery, which resulted in the difficulty of specimen obtainment. To screen and identify new biomarkers in PHCCA, we constructed a retrospective cohort with 121 PHCCA patients and a prospective cohort consisting of 64 PHCCA patients, and screened the candidate biomarkers by immunohistochemistry and quantified PCR. In our study, expression of high mobility group box 1 (HMGB1) was demonstrated to be significantly associated with microvascular density (MVD) and unfavorable prognosis of PHCCA in both retrospective and prospective study. Moreover, HMGB1 concentrations in bile and serum of PHCCA patients and healthy controls were detected and compared. Postoperative serum HMGB1 and reflux cholangitis indicated recurrence and unfavorable prognosis of PHCCA. With experiments in vitro and in vivo, we demonstrated that intracellular HMGB1 could be released from PHCCA cells and induce invasion and angiogenesis with LPS stimulation. VEGFR2 expression in vessel endothelial cells was upregulated by the released HMGB1 from PHCCA, resulting in the ectopic angiogenesis. In conclusion, intracellular HMGB1 could be released from PHCCA cells and promote angiogenesis via elevating VEGFR2 in vessel endothelial cells. High expression of HMGB1 was associated with MVD and poor prognosis in clinical analyzation. Postoperative serum HMGB1 and cholangitis could predict high recurrence and unfavorable prognosis.

Nitrosative stress, as an important oxygen metabolism disorder, has been shown to be closely associated with cardiovascular diseases, such as myocardial ischemia/reperfusion injury, aortic aneurysm, heart failure, hypertension, and atherosclerosis. Nitrosative stress refers to the joint biochemical reactions of nitric oxide (NO) and superoxide (O2–) when an oxygen metabolism disorder occurs in the body. The peroxynitrite anion (ONOO–) produced during this process can nitrate several biomolecules, such as proteins, lipids, and DNA, to generate 3-nitrotyrosine (3-NT), which further induces cell death. Among these, protein tyrosine nitration and polyunsaturated fatty acid nitration are the most studied types to date. Accordingly, an in-depth study of the relationship between nitrosative stress and cell death has important practical significance for revealing the pathogenesis and strategies for prevention and treatment of various diseases, particularly cardiovascular diseases. Here, we review the latest research progress on the mechanisms of nitrosative stress-mediated cell death, primarily involving several regulated cell death processes, including apoptosis, autophagy, ferroptosis, pyroptosis, NETosis, and parthanatos, highlighting nitrosative stress as a unique mechanism in cardiovascular diseases.