Mitochondria spatially and temporally modulate VSMC phenotypes via interacting with cytoskeleton in cardiovascular diseases.

Cardiovascular diseases caused by atherosclerosis (AS) seriously endanger human health, which is closely related to vascular smooth muscle cell (VSMC) phenotypes. VSMC phenotypic transformation is marked by the alteration of phenotypic marker expression and cellular behaviour. Intriguingly, the mitochondrial metabolism and dynamics altered during VSMC phenotypic transformation. Firstly, this review combs VSMC mitochondrial metabolism in three aspects: mitochondrial ROS generation, mutated mitochondrial DNA (mtDNA) and calcium metabolism respectively. Secondly, we summarized the role of mitochondrial dynamics in regulating VSMC phenotypes. We further emphasized the association between mitochondria and cytoskelton via presenting cytoskeletal support during mitochondrial dynamics process, and discussed its impact on their respective dynamics. Finally, considering that both mitochondria and cytoskeleton are mechano-sensitive organelles, we demonstrated their direct and indirect interaction under extracellular mechanical stimuli through several mechano-sensitive signaling pathways. We additionally discussed related researches in other cell types in order to inspire deeper thinking and reasonable speculation of potential regulatory mechanism in VSMC phenotypic transformation.

Pin1/YAP pathway mediates matrix stiffness-induced epithelial-mesenchymal transition driving cervical cancer metastasis via a non-Hippo mechanism.

Cervical cancer metastasis is an important cause of death in cervical cancer. Previous studies have shown that epithelial-mesenchymal transition (EMT) of tumors promotes its invasive and metastatic capacity. Alterations in the extracellular matrix (ECM) and mechanical signaling are closely associated with cancer cell metastasis. However, it is unclear how matrix stiffness as an independent cue triggers EMT and promotes cervical cancer metastasis. Using collagen-coated polyacrylamide hydrogel models and animal models, we investigated the effect of matrix stiffness on EMT and metastasis in cervical cancer. Our data showed that high matrix stiffness promotes EMT and migration of cervical cancer hela cell lines in vitro and in vivo. Notably, we found that matrix stiffness regulates yes-associated protein (YAP) activity via PPIase non-mitotic a-interaction 1 (Pin1) with a non-Hippo mechanism. These data indicate that matrix stiffness of the tumor microenvironment positively regulates EMT in cervical cancer through the Pin1/YAP pathway, and this study deepens our understanding of cervical cancer biomechanics and may provide new ideas for the treatment of cervical cancer.

Investigation of the mechanism of reverse redistribution in thallium-201 myocardial perfusion scintigraphy in patients with suspicion for coronary artery spasm.

BACKGROUND: Reverse redistribution (RR) is one of the features on myocardial perfusion scintigraphy (MPS) in patients with coronary artery spasm (CAS). This study was aimed to explore the mechanism of RR in patients with suspicion for CAS. METHODS AND RESULTS: Thirty patients with RR and suspicion for CAS but without coronary artery stenosis (RR group) and 32 control patients without RR (control group) underwent coronary angiography before and after a dipyridamole administration. Coronary blood flow velocity and myocardial perfusion, as determined by corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) and TIMI myocardial perfusion grade (TMPG), were measured. Coronary angiography showed significantly slower blood flow velocity [CTFC (37 ± 6) frame vs (29 ± 7) frame, P < .01] and lower myocardial perfusion [TMPG (2.08 ± 0.38) grade vs (2.55 ± 0.33) grade, P < .05] in RR-related arteries than in RR-unrelated arteries in the RR group. But, there was no significant difference among different coronary artery branches in the control group. After the injection of dipyridamole, CTFC decreased and TMPG increased in the RR group. The decline in CTFC and the increase in TMPG in RR-related arteries were more significant than those in RR-unrelated ones (28% vs 14% and 45% vs 16%, respectively; both P < .01). The endothelin-1/nitric oxide (NO) ratio was significantly higher in the RR group than in the control group before the injection of dipyridamole (2.79 ± 0.37 vs 1.70 ± 0.19, P < .01). After the injection of dipyridamole, the ratio went down in both groups, but the decline was statistically significant in the RR group (2.42 ± 0.33, P < .05) but not in the control group (1.42 ± 0.19, P < .05). Pearson correlation analysis showed that there was a positive correlation between summed rest scores on MPS and the endothelin-1/NO ratio (r = 0.853, P = .000) as well as CTFC (r = 0.808, P = .000) before the injection of dipyridamole in the RR group. CONCLUSION: Patients with suspicion for CAS may exhibit a mild spasm of RR-related arteries and corresponding microvasculature and a significant imbalance of coronary blood flow velocity and myocardial perfusion at rest between RR-related and RR-unrelated areas. This is overcome by stress-induced hyperemic flow increases and which may account for RR on MPS.

Characteristics of stress tests and symptoms in patients with myocardial bridge and coronary artery spasm.

BACKGROUND: A relationship between coronary artery spasm (CAS) and myocardial bridge (MB) has been noticed. This study was designed to investigate the differences of stress tests and symptoms between CAS patients with or without MB. METHODS: Two hundred and sixteen patients with atypical chest pain who underwent coronary angiography and acetylcholine provocation test were divided into MB group (n=68) and nonmyocardial bridge group (NMB, n=148). The results of acetylcholine test, treadmill exercise electrocardiography, myocardial scintigraphy, and levels of plasma endothelin-1 and nitric oxide were compared between the two groups. RESULTS: Among these atypical chest pain patients, CAS was induced by acetylcholine in 85% MB patients and 53% NMB patients (P<0.001). A positive exercise electrocardiogram was identified in 71% MB patients and 8% NMB patients (P<0.001). Myocardial scintigraphy revealed ischemic changes in 67% MB patients and 9% NMB patients (P<0.001) and reverse redistribution in 87 and 69% (P<0.01), respectively. MB patients experienced exertional chest pain as well as at rest more frequently than NMB patients. Endothelin-1 levels were elevated in MB group complicated with CAS (P<0.01), whereas nitric oxide levels were reduced in the same cohort (P<0.05) compared with NMB group. CONCLUSION: MB might predispose to CAS in which endothelial dysfunction may play a part. CAS patients with MB usually present mixed chest pain and positive stress tests as well as reversal redistribution on myocardial scintigraphy whereas CAS patients without MB displayed chest pain at rest, negative stress test and reversal redistribution.