Homology-directed repair of an MYBPC3 gene mutation in a rat model of hypertrophic cardiomyopathy.

Variants in myosin-binding protein C3 (MYBPC3) gene are a main cause of hypertrophic cardiomyopathy (HCM), accounting for 30% to 40% of the total number of HCM mutations. Gene editing represents a potential permanent cure for HCM. The aim of this study was to investigate whether genome editing of MYBPC3 using the CRISPR/Cas9 system in vivo could rescue the phenotype of rats with HCM. We generated a rat model of HCM ("1098hom") that carried an Mybpc3 premature termination codon mutation (p.W1098x) discovered in a human HCM pedigree. On postnatal day 3, the CRISPR/Cas9 system was introduced into rat pups by a single dose of AAV9 particles to correct the variant using homology-directed repair (HDR). Analysis was performed 6 months after AAV9 injection. The 1098hom rats didn't express MYBPC3 protein and developed an HCM phenotype with increased ventricular wall thickness and diminished cardiac function. Importantly, CRISPR HDR genome editing corrected 3.56% of total mutations, restored MYBPC3 protein expression by 2.12%, and normalized the HCM phenotype of 1098hom rats. Our work demonstrates that the HDR strategy is a promising approach for treating HCM associated with MYBPC3 mutation, and that CRISPR technology has great potential for treating hereditary heart diseases.

Extracellular Vesicle-Conjugated Functional Matrix Hydrogels Prevent Senescence by Exosomal miR-3594-5p-Targeted HIPK2/p53 Pathway for Disc Regeneration.

Nucleus pulposus stem cells (NPSCs) senescence plays a critical role in the progression of intervertebral disc degeneration (IDD). Stem cell-derived extracellular vesicles (EV) alleviate cellular senescence. Whereas, the underlying mechanism remains unclear. Low stability largely limited the administration of EV in vivo. RGD, an arginine-glycine-aspartic acid tripeptide, strongly binds integrins expressed on the EV membranes, allowing RGD to anchor EV and prolong their bioavailability. An RGD-complexed nucleus pulposus matrix hydrogel (RGD-DNP) is developed to enhance the therapeutic effects of small EV (sEV). RGD-DNP prolonged sEV retention in vitro and ex vivo. sEV-RGD-DNP promoted NPSCs migration, decreased the number of SA-ß-gal-positive cells, alleviated cell cycle arrest, and reduced p16, p21, and p53 activation. Small RNA-seq showed that miR-3594-5p is enriched in sEV, and targets the homeodomain-interacting protein kinase 2 (HIPK2)/p53 pathway. The HIPK2 knockdown rescues the impaired therapeutic effects of sEV with downregulated miR-3594-5p. RGD-DNP conjugate with lower amounts of sEV achieved similar disc regeneration with free sEV of higher concentrations in DNP. In conclusion, sEV-RGD-DNP increases sEV bioavailability and relieves NPSCs senescence by targeting the HIPK2/p53 pathway, thereby alleviating IDD. This work achieves better regenerative effects with fewer sEV and consolidates the theoretical basis for sEV application for IDD treatment.

Obesity and atrial fibrillation: a narrative review from arrhythmogenic mechanisms to clinical significance.

The prevalence of obesity and atrial fibrillation (AF), which are inextricably linked, is rapidly increasing worldwide. Obesity rates are higher among patients with AF than healthy individuals. Some epidemiological data indicated that obese patients were more likely to develop AF, but others reported no significant correlation. Obesity-related hypertension, diabetes, and obstructive sleep apnea are all associated with AF. Additionally, increased epicardial fat, systemic inflammation, and oxidative stress caused by obesity can induce atrial enlargement, inflammatory activation, local myocardial fibrosis, and electrical conduction abnormalities, all of which led to AF and promoted its persistence. Weight loss reduced the risk and reversed natural progression of AF, which may be due to its anti-fibrosis and inflammation effect. However, fluctuations in weight offset the benefits of weight loss. Therefore, the importance of steady weight loss urges clinicians to incorporate weight management interventions in the treatment of patients with AF. In this review, we discuss the epidemiology of obesity and AF, summarize the mechanisms by which obesity triggers AF, and explain how weight loss improves the prognosis of AF.

Pirfenidone alleviates cardiac fibrosis induced by pressure overload via inhibiting TGF-ß1/Smad3 signalling pathway.

Cardiac fibrosis critically injured the cardiac structure and function of the hypertensive patients. However, the anti-fibrotic strategy is still far from satisfaction. This study aims to determine the effect and mechanism of Pirfenidone (PFD), an anti-lung fibrosis medicine, in the treatment of cardiac fibrosis and heart failure induced by pressure overload. Male C57BL/6 mice were subjected to thoracic aorta constriction (TAC) or sham surgery with the vehicle, PFD (300 mg/kg/day) or Captopril (CAP, 20 mg/kg/day). After 8 weeks of surgery, mice were tested by echocardiography, and then sacrificed followed by morphological and molecular biological analysis. Compared to the sham mice, TAC mice showed a remarkable cardiac hypertrophy, interstitial and perivascular fibrosis and resultant heart failure, which were reversed by PFD and CAP significantly. The enhanced cardiac expression of TGF-ß1 and phosphorylation of Smad3 in TAC mice were both restrained by PFD. Cardiac fibroblasts isolated from adult C57BL/6 mice were treated by Angiotensin II, which led to significant increases in cellular proliferation and levels of α-SMA, vimentin, TGF-ß1 and phosphorylated TGF-ß receptor and Smad3. These changes were markedly inhibited by pre-treatment of PFD. Collectively, PFD attenuates myocardial fibrosis and dysfunction induced by pressure overload via inhibiting the activation of TGF-ß1/Smad3 signalling pathway.

Trimetazidine enhances myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice through directly activating Akt and promoting the binding of HSF1 to VEGF-A promoter.

Latest clinical research shows that trimetazidine therapy during the perioperative period relieves endothelial dysfunction in patients with unstable angina induced by percutaneous coronary intervention. In this study we investigated the effects of TMZ on myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery. TAC mice were administered trimetazidine (2.8 mg/100 µL, i.g.) for 28 consecutive days. We showed that trimetazidine administration significantly increased blood vessel density in the left ventricular myocardium and abrogated cardiac dysfunction in TAC mice. Co-administration of a specific HSF1 inhibitor KRIBB11 (1.25 mg/100 µL, i.h.) abrogated the angiogenesis-promoting effects of trimetazidine in TAC mice. Using luciferase reporter and electrophoretic mobility shift assays we demonstrated that the transcription factor HSF1 bound to the promoter region of VEGF-A, and the transcriptional activity of HSF1 was enhanced upon trimetazidine treatment. In molecular docking analysis we found that trimetazidine directly bound to Akt via a hydrogen bond with Asp292 and a pi-pi bond with Trp80. In norepinephrine-treated HUVECs, we showed that trimetazidine significantly increased the phosphorylation of Akt and the synergistic nuclear translocation of Akt and HSF1, as well as the binding of Akt and HSF1 in the nucleus. These results suggest that trimetazidine enhances myocardial angiogenesis through a direct interaction with Akt and promotion of nuclear translocation of HSF1, and that trimetazidine may be used for the treatment of myocardial angiogenic disorders in hypertensive patients.

Emerging role of VCP/p97 in cardiovascular diseases: novel insights and therapeutic opportunities.

Valosin-containing protein (VCP/p97) is a member of the conserved type II AAA+ (ATPases associated with diverse cellular activities) family of proteins with multiple biological functions, especially in protein homeostasis. Mutations in VCP/p97 are reportedly related to unique autosomal dominant diseases, which may worsen cardiac function. Although the structure of VCP/p97 has been clearly characterized, with reports of high abundance in the heart, research focusing on the molecular mechanisms underpinning the roles of VCP/p97 in the cardiovascular system has been recently undertaken over the past decades. Recent studies have shown that VCP/p97 deficiency affects myocardial fibers and induces heart failure, while overexpression of VCP/p97 eliminates ischemia/reperfusion injury and relieves pathological cardiac hypertrophy caused by cardiac pressure overload, which is related to changes in the mitochondria and calcium overload. However, certain studies have drawn opposing conclusions, including the mitigation of ischemia/reperfusion injury via inhibition of VCP/p97 ATPase activity. Nevertheless, these emerging studies shed light on the role of VCP/p97 and its therapeutic potential in cardiovascular diseases. In other words, VCP/p97 may be involved in the development of cardiovascular disease, and is anticipated to be a new therapeutic target. This review summarizes current findings regarding VCP/p97 in the cardiovascular system for the first time, and discusses the role of VCP/p97 in cardiovascular disease.

Chinese Society of Cardiology guidelines on the diagnosis and treatment of adult fulminant myocarditis.

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Understanding COVID-19-related myocarditis: pathophysiology, diagnosis, and treatment strategies.

Coronavirus disease 2019 (COVID-19) disease has infected nearly 600 million people, resulting in > 6 million deaths, with many of them dying from cardiovascular diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is caused by a combination of the virus surface spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor. In addition to being highly expressed in the lungs, ACE2 is widely distributed in the heart, mainly in myocardial cells and pericytes. Like other types of viruses, SARS-CoV-2 can cause myocarditis after infecting the myocardial tissue, which is attributed to the direct damage of the virus and uncontrolled inflammatory reactions. Patients with chest tightness, palpitation, abnormal electrocardiogram, and cardiac troponin elevation, should be suspected of myocarditis within 1-3 weeks of COVID-19 infection. When the hemodynamics change rapidly, fulminant myocarditis should be suspected. Cardiac ultrasound, myocardial biopsy, cytokine detection, cardiac magnetic resonance imaging, 18F-fluorodeoxyglucose positron emission tomography, and other examination methods can assist in the diagnosis. Although scientists and clinicians have made concerted efforts to seek treatment and prevention measures, there are no clear recommendations for the treatment of COVID-19-related myocarditis. For most cases of common myocarditis, general symptomatic and supportive treatments are used. For COVID-19-related fulminant myocarditis, it is emphasized to achieve "early identification, early diagnosis, early prediction, and early treatment" based on the "life support-based comprehensive treatment regimen." Mechanical circulatory support therapy can rest the heart, which is a cure for symptoms, and immune regulation therapy can control the inflammatory storms which is a cure for the disease. Furthermore, complications of COVID-19-related myocarditis, such as arrhythmia, thrombosis, and infection, should be actively treated. Herein, we summarized the incidence rate, manifestations, and diagnosis of COVID-19-related myocarditis and discussed in detail the treatment of COVID-19-related myocarditis, especially the treatment strategy of fulminant myocarditis.

Combination of Nicorandil and Beta-Adrenergic Receptor Blockers in Patients with Coronary Artery Disease: A Real-World Observational Study.

BACKGROUND: The effect of combined nicorandil and beta-adrenergic receptor blockers (BBs) compared with that of BBs alone on long-term clinical outcomes in patients with coronary artery disease (CAD) remains undetermined. METHODS: A multicenter retrospective cohort study was performed. Adult patients who had been hospitalized for CAD and treated for angina with a combination of nicorandil and BBs or BBs alone were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular event (MACE) and their components within a follow-up duration of 2.5 years were analyzed using Kaplan-Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. RESULTS: A total of 137,714 patients were screened, of whom 16,912 individuals (mean age: 61.5 years, men: 67.1%) were successfully enrolled. Among the enrolled participants, 4669 received the combined treatment of nicorandil and BBs, while 12,243 received BBs alone. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (hazard ratio [HR] 0.79, 95% conidence interval [CI] 0.72-0.87) and stroke (HR 0.48, 95% CI 0.42-0.54) but not of MI (HR 1.03, 95% CI 0.92-1.15) or all-cause mortality (HR 0.93, 95% CI 0.64-1.37). Sensitivity analyses revealed similar results. CONCLUSIONS: A combined antiangina treatment of nicorandil and BBs may be more effective than treatment of BBs alone in reducing the long-term incidence of MACE in patients with CAD.

COVID-19 and Cardiovascular Diseases: From Cellular Mechanisms to Clinical Manifestations.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), quickly spread worldwide and led to over 581 million confirmed cases and over 6 million deaths as 1 August 2022. The binding of the viral surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor is the primary mechanism of SARS-CoV-2 infection. Not only highly expressed in the lung, ACE2 is also widely distributed in the heart, mainly in cardiomyocytes and pericytes. The strong association between COVID-19 and cardiovascular disease (CVD) has been demonstrated by increased clinical evidence. Preexisting CVD risk factors, including obesity, hypertension, and diabetes etc., increase susceptibility to COVID-19. In turn, COVID-19 exacerbates the progression of CVD, including myocardial damage, arrhythmia, acute myocarditis, heart failure, and thromboembolism. Moreover, cardiovascular risks post recovery and the vaccination-associated cardiovascular problems have become increasingly evident. To demonstrate the association between COVID-19 and CVD, this review detailly illustrated the impact of COVID-19 on different cells (cardiomyocytes, pericytes, endothelial cells, and fibroblasts) in myocardial tissue and provides an overview of the clinical manifestations of cardiovascular involvements in the pandemic. Finally, the issues related to myocardial injury post recovery, as well as vaccination-induced CVD, has also been emphasized.

RBM20, a Therapeutic Target to Alleviate Myocardial Stiffness via Titin Isoforms Switching in HFpEF.

Increased myocardial stiffness is critically involved in heart diseases with impaired cardiac compliance, especially heart failure with preserved ejection fraction (HFpEF). Myocardial stiffness mainly derives from cardiomyocyte- and extracellular matrix (ECM)-derived passive stiffness. Titin, a major component of sarcomeres, participates in myocardial passive stiffness and stress-sensitive signaling. The ratio of two titin isoforms, N2BA to N2B, was validated to influence diastolic dysfunction via several pathways. RNA binding motif protein 20 (RBM20) is a well-studied splicing factor of titin, functional deficiency of RBM20 in mice profile improved cardiac compliance and function, which indicated that RBM20 functions as a potential therapeutic target for mitigating myocardial stiffness by modulating titin isoforms. This minor review summarized how RBM20 and other splicing factors modify the titin isoforms ratio, therefore providing a promising target for improving the myocardial compliance of HFpEF.

Epoxyeicosatrienoic acid: A potential therapeutic target of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) reduces the quality of life, costs substantial medical resources, and has a high mortality. However, we lack an effective therapy for HFpEF due to our limited knowledge of its mechanism. Therefore, it is crucial to explore novel therapeutics, such as those with endogenous protective roles, and seek new targeted therapies. Epoxyeicosatrienoic acids (EETs) are endogenous bioactive metabolites of arachidonic acids produced by cytochrome P450 (CYP) epoxygenases. EETs can function as endogenous cardioprotective factors with potent inhibitory roles in inflammation, endothelial dysfunction, cardiac remodeling, and fibrosis, which are the fundamental mechanisms of HFpEF. This suggests that EETs have the potential function to protect against HFpEF. Therefore, we present an overview of the ever-expanding world of EETs and how they might help alleviate the pathophysiology underlying HFpEF to provide new insights for research in this field.

Clinical Implications of Nicorandil Combined with Trimetazidine in Patients with Coronary Heart Disease: A Real-World Observational Study.

INTRODUCTION: Coronary heart disease (CHD) remains the leading cause of mortality in China. The treatment strategies, especially for patients with ischemic angina pectoris, are still far from satisfactory. Hence, this study was carried out to evaluate the long-term potential of nicorandil in Chinese patients with CHD. METHODS: Adult patients with CHD were reviewed retrospectively from three hospitals in Central China to obtain relevant data. The primary outcome was the rate of major adverse cardiovascular events (MACE) which is the composite outcome of stroke, myocardial infarction (MI), and mortality at 3 years while the secondary outcomes included rates of MACE, stroke, MI, and mortality at 1 and 2 years. The rates of MACE were estimated using Kaplan-Meir survival curves and compared by log-rank test. The association between various treatment regimens and hazards of MACE was estimated using Cox proportional hazards model. All analyses were carried out using SAS 9.4. RESULTS: A total of 5504, 1674, and 3923 patients treated with the nicorandil-trimetazidine combination, nicorandil, and trimetazidine were included in the study, respectively. At 3-year follow-up, the rate of MACE [hazard ratio (HR) 0.85; 95% CI 0.74-0.97; P = 0.017] and stroke (HR 0.58, 95% CI 0.48-0.71; P < 0.0001) was lower in the combination group compared to trimetazidine group. Similarly, the rate of stroke was significantly lower (HR 0.69; 95% CI 0.52-0.93; P = 0.0146) at 3 years in the nicorandil group compared to the trimetazidine group. The rate of stroke (HR 0.65; 95% CI 0.52-0.83; P = 0.0004) was significantly lower among the combination group compared with the trimetazidine group at 1-year follow-up. Similarly, the rate of stroke was significantly lower at 1 year (HR 0.70; 95% CI 0.50-0.97; P = 0.03) but not at 2 years (HR 0.70; 95% CI 0.52-0.94; P = 0.0177), while the rate of other outcomes, though lower in the nicorandil group than the trimetazidine group, was not statistically significant at 1 and 2 years respectively. CONCLUSION: Nicorandil in combination with trimetazidine can be considered as an effective and potential treatment strategy in reducing the rate of MACE in patients with CHD in the Chinese population.

The role of CD36 in cardiovascular disease.

CD36, also known as the scavenger receptor B2, is a multifunctional receptor widely expressed in various organs. CD36 plays a crucial role in the uptake of long-chain fatty acids, the main metabolic substrate in myocardial tissue. The maturation and transportation of CD36 is regulated by post-translational modifications, including phosphorylation, ubiquitination, glycosylation, and palmitoylation. CD36 is decreased in pathological cardiac hypertrophy caused by ischaemia-reperfusion and pressure overload, and increased in diabetic cardiomyopathy and atherosclerosis. Deficiency of CD36 alleviates diabetic cardiomyopathy and atherosclerosis, while overexpression of CD36 eliminates ischaemia-reperfusion damage, together suggesting that CD36 is closely associated with the progression of cardiovascular diseases and may be a new therapeutic target. This review summarizes the regulation and post-translational modifications of CD36 and evaluates its role in cardiovascular diseases and its potential as a therapeutic target.

Emerging Roles of Ceramide in Cardiovascular Diseases.

Ceramide is a core molecule of sphingolipid metabolism that causes selective insulin resistance and dyslipidemia. Research on its involvement in cardiovascular diseases has grown rapidly. In resting cells, ceramide levels are extremely low, while they rapidly accumulate upon encountering external stimuli. Recently, the regulation of ceramide levels under pathological conditions, including myocardial infarction, hypertension, and atherosclerosis, has drawn great attention. Increased ceramide levels are strongly associated with adverse cardiovascular risks and events while inhibiting the synthesis of ceramide or accelerating its degradation improves a variety of cardiovascular diseases. In this article, we summarize the role of ceramide in cardiovascular disease, investigate the possible application of ceramide as a new diagnostic biomarker and a therapeutic target for cardiovascular disorders, and highlight the remaining problems.

Salvianolic Acid Ameliorates Pressure Overload-Induced Cardiac Endothelial Dysfunction via Activating HIF1[Formula: see text]/HSF1/CD31 Pathway.

Pressure overload is a major risk factor for various cardiovascular diseases. Disorders of the endothelium are involved in the pathological mechanisms of pressure, and maintaining endothelial function is a practical strategy to alleviate pressure overload-induced cardiac injury. In this study, we provided evidence that salvianolic acid, the active component of Danshen, a traditional Chinese herb medicine, preserved pressure overload-induced cardiac dysfunction via protecting endothelium. Male C57BL/6J mice were imposed with transverse aortic constriction to mimic pressure overload and treated with salvianolic acid (200[Formula: see text]mg/kg/day) or vehicle for 6 weeks. The hemodynamic and cardiac functional parameters were detected by the cardiac catheter and transthoracic echocardiography. The pathological measurements were conducted by heart hematoxylin-eosin, wheat germ agglutinin staining, Masson's trichrome staining, and immunofluorescence staining. Endothelial cell (EC) proliferation was estimated using the Cell Counting Kit-8, EC migration was evaluated by scratched assay, and EC integrity was observed by electron microscope. Salvianolic acid notably inhibited cardiac chamber enlargement, restrained cardiac contractile dysfunction, and repressed cardiac fibrosis caused by chronic pressure overload. Salvianolic acid maintained endothelial tight junction integrity by boosting the expression of CD31. Furthermore, the endothelial protective effect of salvianolic acid against pressure overload is dependent on the activation of hypoxia-inducible factor 1[Formula: see text], which consequently activated heat shock factor 1 and promoted CD31 expression. Our study uncovered that salvianolic acid protected cardiac ECs against pressure overload via a HIF1[Formula: see text]/HSF1/CD31 pathway, indicating a potential appliance of salvianolic acid in hypertensive heart disease.

N-Acetyl Cysteine Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Intracellular Triglyceride Accumulation by Preserving Mitochondrial Function.

Rationale: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic disease characterized by liver steatosis. Excessive reactive oxygen species (ROS) originating from dysfunctional mitochondria is the major pathophysiological contributor in the development of NAFLD and is thought to be a promising therapeutic target. A few reports demonstrate the antioxidative treatments for NAFLD. Methods: Male C57 mice were fed on a normal chow diet (ND) or high-fat diet (HFD) for 8 weeks. PBS or N-acetyl cysteine (NAC) was gavaged to mice. LO2 human liver cell line treated with palmitic acid (PA) was applied as a cellular model. Western blot, immunofluorescence, biochemistry assay, and pathological staining were used to investigate the mechanism of suppressing lipid accumulation of NAC. Results: NAC treatment was able to prevent HFD-induced NAFLD, as evidenced by less hepatic triglyceride accumulation and lipid droplet formation compared with that of mice in the HFD group. NAC could preserve mitochondrial function by inhibiting excessive mitophagy and promoting mitochondria biogenesis to prevent ROS production. NAC also activated Sirt1 and preserved its protein level and subsequently promoted mitochondria biogenesis via deacetylating PGC1a. Conclusion: We demonstrated that NAC may be an effective drug to treat NAFLD, which was related to its antioxidative and mitochondrial protective effect.

Trimetazidine Attenuates Heart Failure by Improving Myocardial Metabolism via AMPK.

Energic deficiency of cardiomyocytes is a dominant cause of heart failure. An antianginal agent, trimetazidine improves the myocardial energetic supply. We presumed that trimetazidine protects the cardiomyocytes from the pressure overload-induced heart failure through improving the myocardial metabolism. C57BL/6 mice were subjected to transverse aortic constriction (TAC). After 4 weeks of TAC, heart failure was observed in mice manifested by an increased left ventricular (LV) chamber dimension, an impaired LV ejection fraction evaluated by echocardiography analysis, which were significantly restrained by the treatment of trimetazidine. Trimetazidine restored the mitochondrial morphology and function tested by cardiac transmission electron microscope and mitochondrial dynamic proteins analysis. Positron emission tomography showed that trimetazidine significantly elevated the glucose uptake in TAC mouse heart. Trimetazidine restrained the impairments of the insulin signaling in TAC mice and promoted the translocation of glucose transporter type IV (GLUT4) from the storage vesicle to membrane. However, these cardioprotective effects of trimetazidine in TAC mice were notably abolished by compound C (C.C), a specific AMPK inhibitor. The enlargement of neonatal rat cardiomyocyte induced by mechanical stretch, together with the increased expression of hypertrophy-associated proteins, mitochondria deformation and dysfunction were significantly ameliorated by trimetazidine. Trimetazidine enhanced the isolated cardiomyocyte glucose uptake in vitro. These benefits brought by trimetazidine were also removed with the presence of C.C. In conclusion, trimetazidine attenuated pressure overload-induced heart failure through improving myocardial mitochondrial function and glucose uptake via AMPK.

Proper animal experimental designs for preclinical research of biomaterials for intervertebral disc regeneration.

Low back pain is a vital musculoskeletal disease that impairs life quality, leads to disability and imposes heavy economic burden on the society, while it is greatly attributed to intervertebral disc degeneration (IDD). However, the existing treatments, such as medicines, chiropractic adjustments and surgery, cannot achieve ideal disc regeneration. Therefore, advanced bioactive therapies are implemented, including stem cells delivery, bioreagents administration, and implantation of biomaterials etc. Among these researches, few reported unsatisfying regenerative outcomes. However, these advanced therapies have barely achieved successful clinical translation. The main reason for the inconsistency between satisfying preclinical results and poor clinical translation may largely rely on the animal models that cannot actually simulate the human disc degeneration. The inappropriate animal model also leads to difficulties in comparing the efficacies among biomaterials in different reaches. Therefore, animal models that better simulate the clinical charateristics of human IDD should be acknowledged. In addition, in vivo regenerative outcomes should be carefully evaluated to obtain robust results. Nevertheless, many researches neglect certain critical characteristics, such as adhesive properties for biomaterials blocking annulus fibrosus defects and hyperalgesia that is closely related to the clinical manifestations, e.g., low back pain. Herein, in this review, we summarized the animal models established for IDD, and highlighted the proper models and parameters that may result in acknowledged IDD models. Then, we discussed the existing biomaterials for disc regeneration and the characteristics that should be considered for regenerating different parts of discs. Finally, well-established assays and parameters for in vivo disc regeneration are explored.

Glucagon-like peptide-1 receptor activation maintains extracellular matrix integrity by inhibiting the activity of mitogen-activated protein kinases and activator protein-1.

Disruption of the intervertebral disc extracellular matrix (ECM) is a hallmark of intervertebral disc degeneration (IDD), which is largely attributed to excessive oxidative stress. However, there is a lack of clinically feasible approaches to promote the reconstruction of the disc ECM. Glucagon-like peptide-1 (GLP-1), a safe polypeptide hormone adopted to treat type 2 diabetes mellitus, has shown great potential for relieving oxidative stress-related damage. To our knowledge, this is the first study to reveal that exenatide, a GLP-1 receptor (GLP-1R) agonist, can upregulate disc ECM synthesis and attenuate oxidative stress-induced ECM degradation and IDD. Mechanistically, we found that exenatide inhibited the activation of mitogen-activated protein kinases (MAPK) signaling pathway and the formation of BATF/JUNs heterodimers (an index of activator protein-1 (AP-1) activity). The restoration of MAPK signaling activation reversed the protective effects of exenatide and enhanced downstream BATF/JUNs binding. BATF overexpression was also found to aggravate disc ECM damage, even in the presence of exenatide. In summary, exenatide is an effective agent that regulates ECM anabolic balance and restores disc degeneration by inhibiting MAPK activation and its downstream AP-1 activity. The present study provides a therapeutic rationale for activating the GLP-1 receptor against IDD and establishes the important role of AP-1 activity in the pathogenesis of IDD.