Downregulation of salusins alleviates hypertrophic cardiomyopathy via attenuating oxidative stress and autophagy.

INTRODUCTION: Salusins, which are translated from the alternatively spliced mRNA of torsin family 2 member A (TOR2A), play a vital role in regulation of various cardiovascular diseases. However, it remains unclear precisely regarding their roles in hypertrophic cardiomyopathy (HCM). Therefore, this study was conducted to explore therapeutic effect and the underlying mechanisms of salusins on HCM. MATERIAL AND METHODS: In vivo experiments, Sprague-Dawley rats were used to induce HCM model by angiotensin (Ang) II infusion for 4 weeks. The rats were randomly divided into four groups, namely, Saline + Control shRNA (n = 7), Ang II + Control shRNA (n = 8), Saline + TOR2A shRNA (n = 7), and Ang II + TOR2A shRNA groups (n = 8). After HCM induction, doppler echocardiography is recommended to evaluate heart function. In vitro experiments, primary neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (NRCFs) were obtained from newborn rats, and were treated with Ang II (10-6 M) for 24 h. RESULTS: After treatment with Ang II, levels of salusin-α and salusin-ß were elevated in serum and cardiac tissues of rats and in the neonatal rat cardiomyocytes and cardiac fibroblasts. Downregulation of salusins alleviated the Ang II-induced cardiac hypertrophy by suppressing the increased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) and cardiac fibrosis by blocking collagen I, collagen III and transforming growth factor-beta (TGF-ß), and it also attenuated oxidative stress by suppressing the increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels and reversing the decreased superoxide dismutase (SOD) activity and autophagy by inhibiting the increased microtubule-associated protein light chain 3B (LC3B), Beclin1, autophagy related gene (Atg) 3 and Atg5 in the cardiac tissues of Ang II-infused rats and in the Ang II-treated NRCMs. CONCLUSIONS: All these findings suggest that the levels of salusins were elevated in the HCM, and targeting of salusins contributes to alleviation of cardiac hypertrophy and fibrosis probably via attenuating oxidative stress and autophagy. Accordingly, targeting of salusins may be a strategy for HCM therapy.

CTRP12 ameliorates post-myocardial infarction heart failure through down-regulation of cardiac apoptosis, oxidative stress and inflammation by influencing the TAK1-p38 MAPK/JNK pathway.

OBJECTIVE: C1q/tumour necrosis factor-related protein 12 (CTRP12) is closely related to coronary artery disease and has an outstanding cardioprotective effect. However, whether CTRP12 participates in heart failure (HF) has not been well studied. This work aimed to explore the role and mechanism of CTRP12 in post-myocardial infarction (MI) HF. METHODS: Rats were subjected to left anterior descending artery ligation and then raised for six weeks to establish post-MI HF. Recombinant adeno-associated virus-mediated gene transfer was applied to overexpress or silence CTRP12 in rat hearts. RT-qPCR, Immunoblot, Echocardiography, Haematoxylin-eosin (HE) staining, Masson's trichrome staining, TUNEL staining and ELISA were carried out. RESULTS: CTRP12 levels were decreased in the hearts of rats with post-MI HF. The overexpression of CTRP12 improved cardiac function and attenuated cardiac hypertrophy and fibrosis in rats with post-MI HF. CTRP12 silencing exacerbated cardiac dysfunction, hypertrophy and fibrosis in rats with post-MI HF. The cardiac apoptosis, oxidative stress and inflammatory response induced by post-MI HF were weakened by CTRP12 overexpression or aggravated by CTRP12 silencing. CTRP12 inhibited the activation of the transforming growth factor-ß activated kinase 1 (TAK1)-p38 mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway in the hearts of rats with post-MI HF. Treatment with the TAK1 inhibitor reversed the adverse effects of CTRP12 silencing on post-MI HF. CONCLUSIONS: CTRP12 protects against post-MI HF by modulating the TAK1-p38 MAPK/JNK pathway. CTRP12 may be a therapeutic target for the treatment of post-MI HF.

ADSC-derived exosomes attenuate myocardial infarction injury by promoting miR-205-mediated cardiac angiogenesis.

BACKGROUND: Acute myocardial infarction is a major health problem and is the leading cause of death worldwide. Myocardial apoptosis induced by myocardial infarction injury is involved in the pathophysiology of heart failure. Therapeutic stem cell therapy has the potential to be an effective and favorable treatment for ischemic heart disease. Exosomes derived from stem cells have been shown to effectively repair MI injury-induced cardiomyocyte damage. However, the cardioprotective benefits of adipose tissue-derived mesenchymal stem cell (ADSC)-Exos remain unknown. This study aimed to investigate the protective effects of exosomes from ADSC on the hearts of MI-treated mice and to explore the underlying mechanisms. METHODS: Cellular and molecular mechanisms were investigated using cultured ADSCs. On C57BL/6J mice, we performed myocardial MI or sham operations and assessed cardiac function, fibrosis, and angiogenesis 4 weeks later. Mice were intramyocardially injected with ADSC-Exos or vehicle-treated ADSCs after 25 min following the MI operation. RESULTS: Echocardiographic experiments showed that ADSC-Exos could significantly improve left ventricular ejection fraction, whereas ADSC-Exos administration could significantly alleviate MI-induced cardiac fibrosis. Additionally, ADSC-Exos treatment has been shown to reduce cardiomyocyte apoptosis while increasing angiogenesis. Molecular experiments found that exosomes extracted from ADSCs can promote the proliferation and migration of microvascular endothelial cells, facilitate angiogenesis, and inhibit cardiomyocytes apoptosis through miRNA-205. We then transferred isolated exosomes from ADSCs into MI-induced mice and observed decreased cardiac fibrosis, increased angiogenesis, and improved cardiac function. We also observed increased apoptosis and decreased expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in HMEC-1 transfected with a miRNA-205 inhibitor. CONCLUSION: In summary, these findings show that ADSC-Exos can alleviate cardiac injury and promote cardiac function recovery in MI-treated mice via the miRNA-205 signaling pathway. ADSC-Exos containing miRNA205 have a promising therapeutic potential in MI-induced cardiac injury.

Anterior wall myocardial infarction in a 16-year-old man caused by coronary artery aneurysm during the outbreak of COVID-19.

BACKGROUND: Coronary artery aneurysm (CAA) is a potential cause of infarction. During the outbreak of coronavirus disease 2019 (COVID-19), home isolation and activity reduction can lead to hypercoagulability. Here, we report a case of sudden acute myocardial infarction caused by large CAA during the home isolation. CASE PRESENTATION: During the outbreak of coronavirus disease 2019 (COVID-19),a 16-year-old man with no cardiac history was admitted to CCU of Tang du hospital because of severe chest pain for 8 h. The patient reached the hospital its own, his electrocardiogram showed typical features of anterior wall infarction, echocardiography was performed and revealed local anterior wall dysfunction, but left ventricle ejection fraction was normal, initial high-sensitivity troponin level was 7.51 ng/mL (<1.0 ng/mL). The patient received loading dose of aspirin and clopidogrel bisulfate and a total occlusion of the LAD was observed in the emergency coronary angiography (CAG). After repeated aspiration of the thrombus, TIMI blood flow reached level 3. Coronary artery aneurysm was visualized in the last angiography. No stent was implanted. Intravascular ultrasound (IVUS) was performed and the diagnosis of coronary artery aneurysm was further confirmed. The patient was discharged with a better health condition. CONCLUSIONS: Coronary artery aneurysm is a potential reason of infarction, CAG and IVUS are valuable tools in diagnosis in such cases, during the outbreak of coronavirus disease 2019 (COVID-19), home isolation and activity reduction can lead to hypercoagulability, and activities at home should be increased in the high-risk patients.

Low dose tunicamycin enhances atherosclerotic plaque stability by inducing autophagy.

After decades of indolent progression, atherosclerosis may cause unheralded events, such as myocardial infarction, acute coronary syndrome and stroke due to sudden rupture of atherosclerotic plaques, and pharmacologically modulating plaque stability would reduce the risk of cardiovascular diseases. Endoplasmic reticulum stress (ERS) is responsible for the vulnerability of plaques. However, the underlying mechanism has not been fully elucidated. In this work, ApoE(-/-) mice underwent perivascular carotid collar placement surgeries or sham operations were given higher (3.0mg/kg) and lower (0.3mg/kg) doses of tunicamycin (TM), and plaque stability was evaluated. It was shown that lower TM-treated animals exhibited reduced plaque areas and necrotic cores as well as fibrous cap thickness accompanied by a lower percentage of infiltrates and foam cells than the sham-operated and higher TM treated animals. Lower TM had a profound inhibitory effect on plasma inflammatory response and lipid profile in atherosclerotic ApoE(-/-) mice. In addition, we found that the ApoE(-/-) mice presented higher autophagy activity in response to lower TM administration while apoptosis was reduced. An in vitro study in murine macrophages revealed that lower TM could markedly reduce lipid uptake and accumulation and cell apoptosis while significantly upregulated the expression of Atg7. However, higher TM had adverse effects. Finally, mild induction of ERS by lower TM inhibits AKT-TSC-mTOR cascades to increase cellular autophagy. However, high TM failed to enhance autophagy and equilibrate elevated CHOP-mediated cell death in spite of the inhibition of AKT-TSC-mTOR signaling. In conclusion, lower TM stabilized plaques by activating autophagy through AKT-TSC-mTOR signaling.