Calcitonin Inhibits Phenotypic Switching of Aortic Smooth Muscle Cells and Neointimal Hyperplasia through the AMP-Activated Protein Kinase/Mechanistic Target of Rapamycin Pathway.

Calcitonin (CT) is a peptide hormone secreted by the parafollicular C cells of the thyroid gland, salmon calcitonin was originally extracted from the hind cheek of salmon. Neointimal hyperplasia refers to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, a rat model of restenosis was employed to explore the impact of calcitonin on neointima proliferation. Calcitonin was administered via continuous injections for a duration of 14 days postsurgery, and the expression of proteins associated with proliferation, migration, and phenotypic switching was assessed using the vascular smooth muscle cells. Additionally, metabolomic analyses were conducted to shed light on the mechanisms that underlie the role of calcitonin in the development of cardiovascular disease. In our study, we found that calcitonin possesses the capability to dispute the proliferation, migration, and phenotypic transformation of VSMCs induced by platelet-derived growth factor-BB (PDGF-BB) and 15% fetal bovine serum in vitro. Calcitonin has demonstrated a favorable impact on smooth muscle cells, both in vitro and in vivo. More specifically, it has been observed to mitigate phenotypic switching, proliferation, and migration of these cells. Moreover, calcitonin has been identified as a protective factor against phenotypic switching and the formation of neointima, operating through the AMP-activated protein kinase/mechanistic target of rapamycin (mTOR) pathway.

Suramin inhibits phenotypic transformation of vascular smooth muscle cells and neointima hyperplasia by suppressing transforming growth factor beta receptor 1 /Smad2/3 pathway activation.

Vascular smooth muscle cells (VSMCs) contribute to neointimal hyperplasia (NIH) after vascular injury, a common feature of vascular remodelling disorders. Suramin is known to exert antitumour effects by inhibiting the proliferation of various tumour cells; however, its effects and mechanism on VSMCs remain unclear. This study investigated the effects of suramin on human aortic smooth muscle cells (HASMCs), rat aortic smooth muscle cells (RASMCs) and NIH to examine its suitability for the prevention of vascular remodelling disorders. In vitro, suramin administration reduced platelet-derived growth factor type BB (PDGF-BB)-stimulated proliferation, migration, and dedifferentiation of VSMCs through a transforming growth factor beta receptor 1 (TGFBR1)/Smad2/3-dependent pathway. Suramin dramatically inhibited NIH ligation in the left common carotid artery (LCCA) vivo. Therefore, our results indicate that suramin protects against the development of pathological vascular remodelling by attenuating VSMCs proliferation, migration, and phenotypic transformation and may be used as a potential medicine for the treatment of NIH.

Arterial Adventitial Vasa Vasorum Density Reflects The Progression Of Unstable Plaques: A Retrospective Clinical Study.

OBJECTIVE: Arterial adventitial vasa vasorum (AVV) plays an important role in the occurrence and development of atherosclerotic (AS) disease. AS is a systemic disease, and plaque is not only a local vascular event, but also occurs at multiple sites throughout the vascular bed. Currently, effective anti-AVV therapies are lacking. Therefore, we posed the following scientific questions: "does human carotid adventitial vasa vasorum density reflect plaque neovascularization and intimal-media hyperplasia in carotid?"; and "is it possible to reduce human AVV density by sonodynamic therapy (SDT)?" METHODS: A retrospective study was conducted on 160 patients with carotid atherosclerosis. Duplex ultrasound scanning (DUS), contrast-enhanced ultrasound (CEUS), coronary angiography, and coronary CT angiography (CTA) were used for diagnosis and screening. Pearson correlation tests and Receiver operating characteristic (ROC) curve were used to analyze the relationships between AVV hyperplasia, vasa vasorum (VV) hyperplasia and the intima-media thickness (IMT). SDT was developed for the treatment of arterial AVV hyperplasia and AS plaques. RESULTS: The presence of local AVV in carotid unstable plaques correlated with the echogenic properties of the carotid plaque and the extent of plaque progression; Furthermore local AVV hyperplasia in patients with carotid atherosclerotic plaques was associated with acute coronary syndrome (ACS) events; Local AVV hyperplasia in patients with carotid atherosclerotic plaques was associated with coronary artery stenosis. Notably, SDT reduced local AVV hyperplasia and shrank the plaques in human femoral and carotid atherosclerotic lesions. CONCLUSIONS: The presence of AVV in human carotid arteries reflects the severity of carotid and coronary artery AS. Further, SDT can reduce the hyperplasia of local AVV in human femoral and carotid plaques.

Histological and functional assessment of a Takotsubo cardiomyopathy model established by immobilization stress.

INTRODUCTION: Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, resembles acute heart failure syndrome but lacks disease-specific diagnosis and treatment strategies. TTC accounts for approximately 5-6% of all suspected cases of acute coronary syndrome in women. At present, animal models of TTC are often created by large amounts of exogenous catecholamines such as isoproterenol. However, isoproterenol injection cannot fully simulate the onset of stress-induced cardiomyopathy in humans since stress is not an instantaneous event. METHODS: Rats were immobilized for 6 h per day for 1-14 days. To examine whether the TTC model was successful, echocardiography was employed; Elisa detected serum sympathetic activation markers; and the Open-Field test (OFT) was used to analyze behavioral changes in rats after stress. Western blot and histology were used to assess sympathetic remodeling, inflammation levels, and fibrosis; qRT-PCR was used to explore the levels of fibrosis and myocardial hypertrophy. The electrical stability of ventricular was determined by electrophysiological testing. RESULTS: The rats showed severe stress behavior and local sympathetic remodeling of the heart after only 1 day of stress. After 3 days of stress, the induction of ventricular tachyarrhythmia increased prominently. The highest incidence of TTC in rats was at 5 days of immobilization stress. The pathological left ventricular remodeling caused by immobilization (IMO) stress includes inflammatory infiltration, fibrosis, and myocardial hypertrophy. CONCLUSIONS: Our study confirms the hypothesis that IMO stress can mimic Takotsubo cardiomyopathy, and the various effects on the heart depending on the duration of IMO stress. We observed the highest incidence of TTC occurred after 5 days of stress. Furthermore, there is a gradual occurrence of electrical and structural remodeling as the stress duration prolongs.

Latent profile analysis and influencing factors of quality of life in pregnant women with gestational diabetes mellitus.

PURPOSE: Gestational diabetes mellitus (GDM) negatively affects the quality of life of pregnant women and is influenced by several factors. Research to date treats pregnant women with gestational diabetes as a homogeneous group based on their quality of life. We attempted to identify subgroups based on self-reported quality of life and explored variables associated with subgroups. METHODS: From September 1, 2020 to November 29, 2020, pregnant women with GDM from two hospitals in Guangdong Province were selected as subjects by convenience sampling method. Medical records provided sociodemographic data, duration of GDM, pregnancy status, and family history of diabetes. Participants completed validated questionnaires for quality of life, anxiety and depression. Latent profile analysis was used to identify profiles of quality of life in pregnant women with GDM, and then a mixed regression method was used to analyze the influencing factors of different profiles. RESULTS: A total of 279 valid questionnaires were collected. The results of the latent profile analysis showed that the quality of life of pregnant women with GDM could be divided into two profiles: C1 "high worry-high support" group (75.6%) and C2 "low worry-low support" group (24.4%). Daily exercise duration and depression degree are negative influencing factors, making it easier to enter the C1 group (p < 0.05). Disease duration and family history of diabetes are positive influencing factors, making it easier to enter the C2 group (p < 0.05). CONCLUSION: The quality of life of pregnant women with GDM had obvious classification characteristics. Pregnant women with exercise habits and depression are more likely to enter the "high worry-high support" group, and health care providers should guide their exercise according to exercise guidelines during pregnancy and strengthen psychological intervention. Pregnant women with a family history of diabetes and a longer duration of the disease are more likely to fall into the "low worry-low support" group. Healthcare providers can strengthen health education for them and improve their disease self-management abilities.

Sonodynamic therapy reduces cardiomyocyte apoptosis through autophagy activated by reactive oxygen species in myocardial infarction.

Myocardial infarction (MI) is lethal to patients because of acute ischemia and hypoxia leading to cardiac tissue apoptosis. Autophagy played a key role in MI through affecting the survival of cardiomyocytes. LncRNA-MHRT (myosin heavy-chain-associated RNA transcripts) was specific to the heart and cardiomyocytes, and inhibition of lncRNA-MHRT transcription under pathological stimuli could cause cardiac hypertrophy and even heart failure (HF). Sonodynamic therapy (SDT) is a new and developing medical technique that utilizes low-intensity ultrasound to locally activate a preloaded sonosensitizer. Our group previously reported that SDT could regulate autophagy. In this study, we investigated whether SDT could reduce MI-induced cardiomyocyte apoptosis via activating autophagy pathway. SDT improved cardiac function and suppresses MI-induced cardiomyocyte apoptosis. SDT alleviated MI-induced cardiomyocyte apoptosis by improving autophagy. MHRT mediated the inhibiting effect of SDT on cardiomyocyte apoptosis via activating autophagy pathway. Our data reveal a novel effect that SDT protects against MI and confirm that SDT reduces MI-induced cardiomyocyte apoptosis via activating MHRT-mediated-autophagy. Thus, our findings also indicate that SDT may be used as a potential method for treatment of post-myocardial infarction heart failure.

Rapid reduction in plaque inflammation by sonodynamic therapy inpatients with symptomatic femoropopliteal peripheral artery disease:A randomized controlled trial.

BACKGROUND: Inflammation is actively involved in the clinical manifestation of peripheral artery disease (PAD). Sonodynamic therapy (SDT), a novel non-invasive, plaque-based, macrophage-targeted anti-inflammatory regimen for atherosclerosis has the potential to improve walking performance by reducing plaque inflammation. METHODS: This phase-2, randomized, sham-controlled, double-blind clinical trial enrolled 32 participants with symptomatic femoropopliteal PAD. The primary outcome was the 30-day change in the target-to-background ratio (TBR) within the most diseased segment (MDS) of the femoropopliteal artery assessed through positron emission tomography/computed tomography (PET/CT). The secondary outcomes were changes in walking performance, limb perfusion, lesional morphology and quality of life measurements. RESULTS: The mean age was 64.7 years and 63% were male. Thirty-one completed follow-up. SDT significantly decreased the MDS TBR by 0.53 (95% CI, -0.70 to -0.36, P < 0.001) compared with control. Furthermore, SDT increased peak walking time by 118.6 s (95% CI, 74.3 to 163.0, P < 0.001), increased ankle-brachial index by 0.11 (95% CI, 0.07 to 0.14, P < 0.001), decreased lesional diameter and area stenosis by 7.2% (95% CI, -8.6 to -4.5, P < 0.001) and 9.6% (95% CI, -24.5 to -5.3, P = 0.005), respectively, and increased the walking speed score of the Walking Impairment Questionnaire by 16.1 (95% CI, 2.6 to 29.5, P = 0.021) and the physical functioning score of the 36-item Short-Form Health Survey by 10.0 (95% CI, 5.0 to 20.0, P = 0.003) compared with control. These improvements were maintained in the SDT group up to 6-month. CONCLUSIONS: SDT rapidly reduced plaque inflammation and improved walking performance among patients with symptomatic PAD. TRIAL REGISTRATION: Clinical Trials NCT03457662.

Sonodynamic Therapy Suppresses Neovascularization in Atherosclerotic Plaques via Macrophage Apoptosis-Induced Endothelial Cell Apoptosis.

During atherosclerosis plaque progression, pathological intraplaque angiogenesis leads to plaque rupture accompanied by thrombosis, which is probably the most important cause of arteries complications such as cerebral and myocardial infarction. Even though few treatments are available to mitigate plaque rupture, further investigation is required to develop a robust optimized therapeutic method. In this study using rabbit and mouse atherosclerotic models, sinoporphyrin sodium (DVDMS)-mediated sonodynamic therapy reduced abnormal angiogenesis and plaque rupture. Briefly, DVDMS is injected to animals, and then the plaque was locally exposed to pulse ultrasound for a few minutes. Furthermore, a small size clinical trial was conducted on patients with atherosclerosis. Notably, a significant reduction of arterial inflammation and angiogenesis was recorded following a short period of DVDMS-mediated sonodynamic therapy treatment. This beneficial outcome was almost equivalent to the therapeutic outcome after 3-month intensive statin treatment.

ß3 adrenergic receptor antagonist SR59230A exerts beneficial effects on right ventricular performance in monocrotaline-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a high mortality rate. Previous studies have revealed the important function of the ß3 adrenergic receptor (ß3-AR) in cardiovascular diseases, and the potential beneficial effects of numerous ß3-AR agonists on pulmonary vasodilation. Conversely, a number of studies have proposed that the antagonism of ß3-AR may prevent heart failure. The present study aimed to investigate the functional involvement of ß3-AR and the effects of the ß3-AR antagonist, SR59230A, in PAH and subsequent heart failure. A rat PAH model was established by the subcutaneous injection of monocrotaline (MCT), and the rats were randomly assigned to groups receiving four weeks of SR59230A treatment or the vehicle control. SR59230A treatment significantly improved right ventricular function in PAH in vivo compared with the vehicle control (P<0.001). Additionally, the expression level of ß3-AR was significantly upregulated in the lung and heart tissues of PAH rats compared with the sham group (P<0.01), and SR59230A treatment inhibited this increase in the lung (P<0.05), but not the heart. Specifically, SR59230A suppressed the elevated expression of endothelial nitric oxide and alleviated inflammatory infiltration to the lung under PAH conditions. These results are, to the best of our knowledge, the first to reveal that SR59230A exerts beneficial effects on right ventricular performance in rats with MCT-induced PAH. Furthermore, blocking ß3-AR with SR59230A may alleviate the structural changes and inflammatory infiltration to the lung as a result of reduced oxidative stress.

Rapid inhibition of atherosclerotic plaque progression by sonodynamic therapy.

Aims: Currently, efficient regimens to reverse atherosclerotic plaques are not available in the clinic. Herein, we present sonodynamic therapy (SDT) as a novel methodology to rapidly inhibit progression of atherosclerotic plaques. Methods and results: In atherosclerotic rabbit and apoE-deficient mouse models, SDT efficiently decreased the atherosclerotic burden within 1 week, revealing a decrease in the size of the atherosclerotic plaque and enlarged lumen. The shrunken atherosclerotic plaques displayed compositional alterations, with a reduction in lesional macrophages and lipids. The rapid efficacy of SDT may be due to its induction of macrophage apoptosis, enhancement of efferocytosis, and amelioration of inflammation in the atherosclerotic plaque. Compared with atorvastatin, the standard of care for atherosclerosis, SDT showed more significant plaque shrinkage and lumen enlargement during 1 week treatment. Furthermore, SDT displayed good safety without obvious side effects. In a pilot clinical trial recruiting the patients suffering atherosclerotic peripheral artery disease, combination therapy of SDT with atorvastatin efficiently reduced progression of atherosclerotic plaque within 4 weeks, and its efficacy was able to last for at least 40 weeks. Conclusion: SDT is a non-invasive and efficacious regimen to inhibit atherosclerotic plaque progression.

Identification of drug repurposing candidates based on a miRNA-mediated drug and pathway network for cardiac hypertrophy and acute myocardial infarction.

BACKGROUND: Cardiac hypertrophy and acute myocardial infarction (AMI) are two common heart diseases worldwide. However, research is needed into the exact pathogenesis and effective treatment strategies for these diseases. Recently, microRNAs (miRNAs) have been suggested to regulate the pathological pathways of heart disease, indicating a potential role in novel treatments. RESULTS: In our study, we constructed a miRNA-gene-drug network and analyzed its topological features. We also identified some significantly dysregulated miRNA-gene-drug triplets (MGDTs) in cardiac hypertrophy and AMI using a computational method. Then, we characterized the activity score profile features for MGDTs in cardiac hypertrophy and AMI. The functional analyses suggested that the genes in the network held special functions. We extracted an insulin-like growth factor 1 receptor-related subnetwork in cardiac hypertrophy and a vascular endothelial growth factor A-related subnetwork in AMI. Finally, we considered insulin-like growth factor 1 receptor and vascular endothelial growth factor A as two candidate drug targets by utilizing the cardiac hypertrophy and AMI pathways. CONCLUSION: These results provide novel insights into the mechanisms and treatment of cardiac hypertrophy and AMI.

Inhalation of Hydrogen Attenuates Progression of Chronic Heart Failure via Suppression of Oxidative Stress and P53 Related to Apoptosis Pathway in Rats.

Background: Continuous damage from oxidative stress and apoptosis are the important mechanisms that facilitate chronic heart failure (CHF). Molecular hydrogen (H2) has potentiality in the aspects of anti-oxidation. The objectives of this study were to investigate the possible mechanism of H2 inhalation in delaying the progress of CHF. Methods and Results: A total of 60 Sprague-Dawley (SD) rats were randomly divided into four groups: Sham, Sham treated with H2, CHF and CHF treated with H2. Rats from CHF and CHF treated with H2 groups were injected isoprenaline subcutaneously to establish the rat CHF model. One month later, the rat with CHF was identified by the echocardiography. After inhalation of H2, cardiac function was improved vs. CHF (p < 0.05), whereas oxidative stress damage and apoptosis were significantly attenuated (p < 0.05). In this study, the mild oxidative stress was induced in primary cardiomyocytes of rats, and H2 treatments significantly reduced oxidative stress damage and apoptosis in cardiomyocytes (p < 0.05 or p < 0.01). Finally, as a pivotal transcription factor in reactive oxygen species (ROS)-apoptosis signaling pathway, the expression and phosphorylation of p53 were significantly reduced by H2 treatment in this rat model and H9c2 cells (p < 0.05 or p < 0.01). Conclusion: As a safe antioxidant, molecular hydrogen mitigates the progression of CHF via inhibiting apoptosis modulated by p53. Therefore, from the translational point of view and speculation, H2 is equipped with potential therapeutic application as a novel antioxidant in protecting CHF in the future.

Improvement of increased cQTd is associated with heart function in patients with ischemic heart failure.

BACKGROUND: Chronic heart failure (CHF) is life-threatening without timely or effective intervention. In this study, we investigated the association between QT dispersion corrected for heart rate (cQTd) and heart function in patients with CHF. METHODS: From January 2013 to December 2015, we continuously enrolled 240 patients categorized as New York Heart Association functional class (NYHA) III-IV with a left ventricular ejection fraction (LVEF) < 40%. Based on the etiology, the patients were divided into a dilated cardiomyopathy (DCM) group (n = 120) and an ischemic cardiomyopathy (ICM) group (n = 120). Then, based on the cQTd width, the ICM group was divided into two subgroups: a QS group (cQTd ≤ 60 ms, n = 70) and a QL group (cQTd > 60 ms, n = 50). All patients were examined by echocardiography and 12-lead electrocardiography (ECG) at 1, 3, 6, and 12 months after enrollment. RESULTS: After one year of optimized medical treatment, patients in both groups showed significant improvement in LVEF and NYHA classification from baseline. However, the cQTd in the ICM group, especially the QL, was significantly shorter than that in the DCM group at each time point. In addition, the cQTd was negatively correlated with LVEF and 6-min walking test and positively correlated with NYHA class in the ICM group. CONCLUSIONS: The present findings clearly demonstrate that cQTd is a meaningful parameter for assessing heart function in the follow-up of ICM patients.

Enhanced ADAM17 expression is associated with cardiac remodeling in rats with acute myocardial infarction.

AIM: This study aimed to investigate the dynamic expression of A-disintegrin-and-metalloproteinase-17 (ADAM17) during cardiac remodeling after acute myocardial infarction (AMI). MAIN METHODS: Forty male Wistar rats with a permanent ligation of the left anterior descending artery were equally divided into four groups based on predefined sacrifice time: MI1d, MI1w, MI4w and MI12w. As controls, 36 rats only with left thoracotomy were equally divided into four groups. Cardiac remodeling was assessed by echocardiography and hematoxylin and eosin (H&E) staining. ADAM17 mRNA was detected by real-time reverse transcription polymerase chain reaction, and protein expression of ADAM17, tissue inhibitor of metalloproteinases-3 (TIMP-3) and TNF-α was analyzed by western blotting. KEY FINDINGS: The systolic function was sharply worsened in the MI1w group (versus the Con1w group, P<0.05), but left ventricular weight index was significantly increased after 4weeks post-MI (P<0.05). H&E staining revealed that one week after AMI, myocardial tissue in the epicardial border zone of the infarcted heart was mixed with broken mitochondrial cristae and decreased matrix density. ADAM17 mRNA and protein expression was significantly increased, accompanied by decreased TIMP-3 and upregulated TNF-α expression in the MI1w group (versus the MI1d group, all P<0.05). Moreover, dynamic ADAM17 mRNA expression was positively correlated with enlarged LVEDd and LVESd (P=0.001, P=0.003) and negatively with LVEF (P=0.039) in AMI rats. SIGNIFICANCE: Enhanced ADAM17 expression, along with decreased TIMP-3 and increased TNF-α expression, especially within one week after AMI, is associated with cardiac remodeling.