Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells

Purpose Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. Methods Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. Results PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy—(ANP and BNP), myocardial fibrosis—(collagen I and TGF-β1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. Conclusion PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Graphical abstract Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1β, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.

Dangshen Erling Decoction Ameliorates Myocardial Hypertrophy via Inhibiting Myocardial Inflammation

Myocardial hypertrophy plays an essential role in the structural remodeling of the heart and the progression to heart failure (HF). There is an urgent need to understand the mechanisms underlying cardiac hypertrophy and to develop treatments for early intervention. Dangshen Erling decoction (DSELD) is a clinically used formula in Chinese medicine for treating coronary heart disease in patients with HF. However, the mechanism by which DSELD produces its cardioprotective effects remains largely unknown. This study explored the effects of DSELD on myocardial hypotrophy both in vitro and in vivo. In vitro studies indicated that DSELD significantly (p < 0.05) reduced the cross-sectional area of the myocardium and reduced elevated lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels in the induced H9C2 cell model to study inflammation. In vivo experiments revealed that DSELD restores cardiac function and significantly reduces myocardial fibrosis in isoproterenol (ISO)-induced HF mouse model (p < 0.05). In addition, DSELD downregulated the expression of several inflammatory cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), IL-1α, IL-1β, IL-3, IL-5, IL-7, IL-12, IL-13, and TNF-α in HF (p < 0.05). Further analysis of the cardiac tissue demonstrated that DSELD produces its anti-inflammatory effects via the Toll-like receptor (TLR)4 signaling pathway. The expression of TLR4 downstream proteins such as matrix metalloproteinase-9 (MMP9) and myeloid differentiation factor-88 (MyD88) was among the regulated targets. In conclusion, these observations suggest that DSELD exerts antihypertrophic effects by alleviating the inflammatory injury via the TLR4 signaling pathway in HF and thus holds promising therapeutic potentials.

Differential Regulation of Myocardial E3 Ligases and Deubiquitinases in Ischemic Heart Failure

The pathological changes of ubiquitination and deubiquitination following myocardial infarction (MI) and chronic heart failure (CHF) have been sparsely examined. We investigated the expression of muscle-specific E3 ubiquitin ligases and deubiquitinases in MI and CHF. Therefore, mice were assigned to coronary artery ligation for 3 days or 10 weeks as well as for sham operation (each n = 10). Expression of E3 ligases (MAFBX, MURF1, CHIP, ITCH, MDM2) and deubiquitinases (A20, CYLD, UCH-L1, USP14, USP19) was determined. After MI and in CHF, the mRNA expression of MURF1, CHIP and MDM2 (all p < 0.05) was decreased. Protein expression analyses revealed that ITCH expression decreased in CHF (p = 0.01), whereas MDM2 expression increased in MI (p = 0.02) and decreased in CHF (p = 0.02). Except for USP19 mRNA expression that decreased at 3 days and 10 weeks (both p < 0.01), the expression of other deubiquitinases remained unaffected after MI and CHF. The expression of myocardial E3 ligases is differentially regulated following MI, raising the question of whether an upstream regulation exists that is activated by MI for tissue protection or whether the downregulation of E3 ligases enables myocardial hypertrophy following MI.

Real Ambient Particulate Matter-Induced Myocardial Hypertrophy and Myocardial Lipotoxicity : Roles of PDGFRβ Methylation

Background: PM exposure can lead to myocardial hypertrophy, with a potential contribution via DNA methylation. Myocardial lipotoxicity is closely related to myocardial hypertrophy. But, myocardial lipotoxicity caused by PM has not been reported. PDGFRβ, a platelet-derived growth factor receptor, is also essential for normal cardiovascular development. However, It is unclear the role of PM-induced PDGFRβ methylation in myocardial hypertrophy and myocardial lipotoxicity. We investigated the effect of PDGFRβ methylation induced by PM on myocardial hypertrophy and myocardial lipotoxicity. Results: PDGFRβ methylation caused by PM decreased PDGFRβ mRNA and protein expression in C57BL/6J mouse hearts. Thus inhibiting gene expression in its downstream pathway, ultimately leading to cardiac hypertrophy. Disturbances of myocardial lipid metabolism caused by PM in AC16 cells and C57BL/6J mouse hearts were also observed. High expression of PDGFRβ in neonatal rat primary cardiomyocytes was found to activate its downstream pathway and ameliorate the effects of PM-induced cardiac hypertrophic activity. At the same time, adenovirus was used to induce high expression of PDGFRβ in C57BL/6J mice. It was found that PDGFRβ not only improved PM-induced cardiac hypertrophy, but also alleviated PM-induced myocardial lipotoxicity. Conclusions: PDGFRβ gene methylation may be one of the potential biomarkers of myocardial hypertrophy induced by PM exposure. And high expression of PDGFRβ may be a potential way to prevent myocardial hypertrophy and cardiac lipid metabolism disorder caused by PM exposure in mice.

Correlations of myocardial bridges with left ventricle myocardial hypertrophy and prepontin coronary atherosclerosis

Background: Of particular interest are the studies researching the correlations of myocardial bridges with hypertrophic cardiomyopathy and correlations of thick myocardial bridges with the development of coronary atherosclerosis in the proximal to the bridge arterial part. Material and methods: Assessment of the correlation between myocardial bridges, coronary atherosclerosis, and the degree of hypertrophy of the left ventricle was performed by retrospective analysis of 6168 coronary angiography protocols (2012-2019) and echocardiographic data from patients’ clinical records. Results: Moderate systolic compression predominated, and the number of patients detected with severe under the bridge systolic coronary stenosis was double as in patients with nonsignificant coronary atherosclerosis. From the total number, patients with myocardial hypertrophy and myocardial bridges were twice less when compared with the patients with the normal myocardial thickness. The comparative research did not show any interdependence between the degree of vascular compression and the degree of left ventricular myocardial hypertrophy. Proximal to the bridges atherosclerosis was detected in 32% of cases without correlation with the force of the myocardial bridge. Conclusions: The study showed the absence of the correlation between the degree of arterial stenosis caused by the bridge and the degree of hypertrophy of the ventricular myocardium as well as the degree of proximal to the bridge atherosclerosis. Important finding was that the degree of coronary systolic compression is higher in patients with moderate and severe proximal to the bridge atherosclerosis.

mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats

Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly im) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8mg/kg/day Vs 1.5mg/kg/day Vs 2mg/kg/day ip) in OVX+ estrogens(E 9.6 mg/Kg/day, ig)+T group was further evaluated. After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length (TL), area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, β- myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor (mTOR), ribosomal protein S6 kinase (S6K1),4E-bindiong protein 1(4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy

Retrospective review: congenital pulmonary artery stenosis in dogs (prevalence forms)

Objective: to determine the occurrence and clinical characteristics of different types of PS (pulmonary stenosis) in dogs Reseach tasks: to identify the breed predisposition to PS, to study the clinical, echocardiographic and electrocardiographic characteristics of various types of PS and to analyse their dependence on the severity of the heart defect. Materials and methods: a retrospective analysis of Biocontrol veterinary clinic medical records throughout six years (2014–2020). Cardiological examination of dogs presented to the primary ambulatory appointment included physical examination, echocardiography using the Philips HD15 ultrasound system, radiography and electrocardiography. Animals: 31 dogs with isolated pulmonary artery stenosis (17 males and 14 females). Breeds: French Bulldog, English Bulldog, Yorkshire Terrier, German Spitz, American Pit Bull Terrier, Staffordshire Terrier, Toy Terrier, Cane Corso, Whippet, Biewer Yorkshire Terrier, Chihuahua, Entlebucher, German Boxer, East European Shepherd, American Bully. Results and discussion: 43 dogs with a PS were examined from 1 January 2014 to 31 December 2020. Of these, 31 dogs (72 %) with isolated PS and 12 dogs (28 %) with a combination of PS with other congenital heart defects. The most common combinations were PS with aortic stenosis (25 %) and PS with ventricular septal defect (25 %). The most common form of isolated PS was type A valve stenosis (68 %). Severe stenosis prevailed (58 %). The most common breeds were French Bulldogs (22.6 %), English Bulldogs (16.1 %) and Yorkshire Terriers (9.7 %). Males were more prevalent (55 %). 61 % of animals from the group of dogs with severe PS visited clinic because of signalment, and syncope was the most frequently reported symptom (28 %). The symptoms associated with congenital heart defect were not identified in the group of animals with moderate and mild degrees of PS. ECG showed that 100 % of dogs were diagnosed with sinus rhythm. Electrical right axis deviation of the heart was detected in 45 % of dogs. Direct dependency was between the severity of the stenosis and the severity of electrical right axis deviation. According to echocardiographic studies — 100 % of animals with severe and moderate stenosis and 14% with mild stenosis were diagnosed with concentric, eccentric or mixed forms of right ventricle myocardial hypertrophy, enlargement of the right atrial. Direct dependency is founded between the severity of stenosis, the type of right ventricle hypertrophy and the size of the right atrium. The more severe stenosis, the more mixed form of hypertrophy; increase of the right atrium was recorded in dogs with mixed right ventricular hypertrophy. Post-stenotic dilatation of the trunk and branches of the pulmonary artery was determined in all dogs with single right coronary artery type R2A. Conclusions: PS is most commonly found in French Bulldogs. The most common type of PS is type A valvular stenosis in the form of an isolated defect. Severe PS is prevalent. There is direct dependency is between the severity of the defect and the severity of right ventricular myocardial hypertrophy, the large size of the right atrium and electrical right axis deviation of the heart.