Development Of Hypertrophy Research Articles

Exosomes derived from cardiac fibroblasts with angiotensin II stimulation provoke hypertrophy and autophagy inhibition in cardiomyocytes

Although accumulating evidence has revealed that autophagy inhibition contributes to the development of pathological cardiac hypertrophy, the mechanisms leading to declined autophagy activity in the hypertrophic heart remain to be elucidated. Exosomes are known to be important mediators of intercellular communication, and the involvement of exosomes in cardiovascular abnormities has attracted increasing attentions. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. Here, we investigated the potential role of CFs-derived exosomes in regulating cardiomyocyte hypertrophy and autophagy. Exosomes from rat CFs treated with angiotensin II (Ang II-CFs-exosomes) were collected and characterized. Our experiments showed that these exosomes could induce hypertrophic responses and impair autophagy activity in primary neonatal rat cardiomyocytes (NRCMs). Ang II-CFs-exosomes blocked the autophagic flux of NRCMs via inhibiting the formation of autolysosomes. Moreover, the pro-hypertrophic effects and autophagy inhibition induced by Ang II-CFs-exosomes was validated in mice receiving injection of the exosomes. These findings highlight a novel role of Ang II-CFs-exosomes in suppressing cardiomyocyte autophagy, which may help to better understand the pathogenesis of cardiac hypertrophy.

FRI491 The Impact Of Insulin Resistance On Thyroid Function In Pregnancy

Abstract Disclosure: M. Trofimiuk-Muldner: None. A.J. Nowak: None. J. Podlewski: None. A. Hubalewska-Dydejczyk: None. The influence of hyperinsulinemia on thyroid function is debatable. Insulin as an anabolic hormone may be responsible for thyroid hypertrophy and nodular development. The interplay between insulin and the function of the pituitary-thyroid axis may influence thyroid tests’ results and their interpretation. This study evaluated the association between thyroid hormones and insulin resistance in pregnant women. The study group was recruited from the Polish National Program for Elimination of Iodine Deficiency, conducted between 2007-2017. We assessed the fasting glucose, insulin levels, thyroid hormones (TSH, FT4, FT3), and ATPO antibodies in 1069 pregnant women (median age 29 years, IQR 6 years). Based on calculated HOMA-IR, participants were stratified into three subgroups HOMA1 (324 women with HOMA-IR < 1), HOMA 2 (570 women with HOMA-IR ≥1& <2.5) and HOMA3 (175 women with HOMA-IR ≥ 2.5). Results: Median (IQR) TSH concentrations were 1.42 (1.33) mIU/L, 1.65 (1.31) mIU/L, and 1.77 (1.29) mIU/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. Median (IQR) FT4 concentrations were 12.9 (3.0) pmol/L, 12.48 (2.85) pmol/L, and 11.38 (2.8) pmol/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. Median (IQR) FT3 concentrations were 4.79 (1.75) pmol/L, 4.6 (1.02) pmol/L, and 4.47 (0.88) pmol/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. Median (IQR) aTPO concentrations were 10 (11.34) IU/L, 11.59 (8.54) IU/L, and 10.15 (7.5) mIU/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. HOMA1 and HOMA2 subgroups differed significantly in TSH (p=0.026) and FT3concentrations (p=0.001). HOMA2 and HOMA3 subgroups differed significantly in FT4 (p<0.001) and aTPO concentrations (p=0.045). HOMA1 and HOMA3 patients differed in TSH (p=0.001), FT4 (p<0.001), and FT3 (p=0.001) concentrations. aTPO-positivity was not related to HOMA-IR values (mean HOMA-IR in aTPO-positive andaTPO-negative women were 1.63 and 1.80 respectively, p=0.32). Conclusions: Insulin resistance may impact thyroid function in pregnancy independently of thyroid autoimmunity, with higher TSH and lower thyroid hormones concentrations in pregnant women with higher HOMA-IR indices. Presentation: Friday, June 16, 2023

Efficacy of Flavonoid Apigenin on Hemodynamic indices, Baroreflex Function, Cardiac and Kidney Remodeling and Vasoactive-Inflammatory Biomarkers in Experimental Renal Hypertension

The hypothesis stated here that, the long-term prevention by natural flavonoid phenolic compound, for example apigenin (Apg), improves baroreflex sensitivity and vascular resistance and occurs beneficial action for attenuation the renal hypertension (RH). One-kidney, 1-clip rats (1K1C) were treated with Apg for 2 weeks after 1 week of surgical intervention. At the end of the study in the control RH group the blood pressure (BP) increased on average by 43.5%, decreased in heart period (HP) by 9.8%, cardiochronotropic (vagal) component of baroreflex sensitivity (BRS) by 50%, and adrenergic component by 34%. Thus, in 1K1C experimental model of hypertension, provides switching to parasympathetic component and accompanied with proportionally nearly two-fold increase in epinephrine (EPN) and norepinephrine (NE) without changes in EPN/NE ratio. Morphometric changes in the kidney and heart confirmed the development of kidney and cardiac hypertrophy and renal functioning disturbances (blood urea nitrogen (BUN) increased in more than two-fold) and markers of sodium reabsorption in proximal tubule, total trans-EETs, decreased in 1.6-fold. The pronounced increased proinflammatory cytokines, interleukin 1b (IL1 b), endothelin -1 (ET-1) and tumor necrosis factor (TNF)-a confirmed the formation of “sterile inflammation” which strengthening by the nearly two-fold decreasing in the level of anti-inflammatory (vasodilatory) mediators, prostaglandin E2 (PGE2). Preventive long-term regime treatment with Apg (5mg/kg i.p./daily) in RH rats significantly decreased BP by 18.6%, increased parasympathetic component of BRS by 38.5% without marked altered its sympathetic component. Such deremodeling in BRS sensitivity associated with significant decreased in heart and kidney hypertrophy and functional activity of kidney, normalization of BUN and total EETs, reducing in circulating plasma level of catecholamines, and markedly attenuated progression of inflammation, decreased of proinflammatory levels of cytokines. Thus, Apg provides preventive beneficial pluripotent action in RH rats by exerting antihypertensive, cardio- and renoprotective effects and attenuation of “sterile inflammation”.

Polymorphism of the coding gene LGALS-3 rs2274273 as an endogenous factor of the predictive effectiveness of the plasma concentration of galectin-3 in relation to the risk of development of chf on the background of eh in women

Objective. The purpose of the study is to improve the early diagnosis of the development of left ventricular myocardial hypertrophy (LVH) and the formation of prerequisites for chronic heart failure (CHF) in women with essential hypertension, residents of the Podillya region of Ukraine by determining the plasma concentration of galectin-3 in carriers of different polymorphic variants of the LGALS-3 (rs2274273) gene. Material and methods. 180 women of postmenopausal age, average age of 57.34±0.45, residents of the Podillya region of Ukraine, who lived in this territory in the third generation, were examined. The control group consisted of 67 women, average age of 56.43±0.64 years, without signs of cardiovascular pathology and signs of left ventricular hypertrophy (LVH) for other reasons were detected. The main group included 113 women with essential hypertension, of which 62 had essential hypertension with LVH without heart failure (EH II), 51 had essential hypertension with chronic heart failure stage C according to the ESH/ESC 2023 classification. General clinical examination, enzyme immunoassay method for determining the level of galectin-3 in blood plasma, genotyping of the LGALS3 (rs2274273) gene using polymerase chain reaction, and ultrasound of the heart were performed. The statistical processing of the obtained results was carried out using the package of statistical programs SPSS, STATISTICA v. 10.0. Mathematical methods were used: multiple regression stepwise analysis of proportional risks with 95% CI confidence interval, Fisher's linear discriminant analysis with the creation of a mathematical prognostic model, and cluster analysis. Compliance of the frequency distribution of genotypes in the studied populations to the Hardy-Weinberg equilibrium was checked using the MedCalc Software Ltd. Odds ratio calculator. https://www.medcalc.org/calc/odds_ratio.php and calculated the odds ratio (OR) of developing left ventricular myocardial hypertrophy (LVH) and chronic heart failure (CHF).Results. In patients with EH and CHF, carrying the A allele of the LGALS-3 (rs2274273) gene was associated with a more severe degree of diastolic dysfunction and reduced LVEF compared with carriers of the GG genotype, and higher plasma levels of galectin-3 were also recorded, which were associated with a more significant deterioration structural and functional indicators of the myocardium. With the help of cluster analysis, it was found that carriers of the A allele of the LGALS-3 (rs2274273) gene are more likely to be included in unfavorable cluster 1. In contrast, in cluster 2, with a more favorable course of the disease, carriers of the GG genotype and carriers of the A allele occur with almost the same frequency. Conclusions. In postmenopausal women, residents of the Podillya region of Ukraine, carrying the A allele of the LGALS-3 (rs2274273) gene is associated with a more severe course of EH with the development of LVH, a higher concentration of galectin-3 in the blood plasma, and the formation of CHF with reduced LVEF when compared with carriers of the genotype GG.

Adaptive and maladaptive roles of different angiotensin receptors in the development of cardiac hypertrophy and heart failure.

Angiotensin II (Ang II) is formed by the action of angiotensin-converting enzyme (ACE) in the renin-angiotensin system. This hormone is known to induce cardiac hypertrophy and heart failure and its actions are mediated by the interaction of both pro- and antihypertrophic Ang II receptors (AT1R and AT2R). Ang II is also metabolized by ACE 2 to Ang-(1-7), which elicits the activation of Mas receptors (MasR) for inducing antihypertrophic actions. Since heart failure under different pathophysiological situations is preceded by adaptive and maladaptive cardiac hypertrophy, we have reviewed the existing literature to gain some information regarding the roles of AT1R, AT2R, and MasR in both acute and chronic conditions of cardiac hypertrophy. It appears that the activation of AT1R may be involved in the development of adaptive and maladaptive cardiac hypertrophy as well as subsequent heart failure because both ACE inhibitors and AT1R antagonists exert beneficial effects. On the other hand, the activation of both AT2R and MasR may prevent the occurrence of maladaptive cardiac hypertrophy and delay the progression of heart failure, and thus therapy with different activators of these antihypertrophic receptors under chronic pathological stages may prove beneficial. Accordingly, it is suggested that a great deal of effort should be made to develop appropriate activators of both AT2R and MasR for the treatment of heart failure subjects.

Терапия ксеногенным протеомным комплексом из эмбриональных клеток головного мозга тормозит прогрессирование экспериментально вызванной хронической почечной недостаточности.

Introduction. In previously published experimental studies, we have shown that in rats with pre-modeled acute post-ischemic renal failure, therapy with a proteomic complex isolated from brain cells of pig embryos has a pronounced therapeutic effect, reducing the severity of functional and histological disorders and preventing the transition of the pathological process into chronic kidney insuffiency. The aim of this study is to evaluate the effectiveness of this therapy for the course of artificially induced chronic renal failure (CRF) in rats. Material and methods. Experiments were carried out on 45 white mongrel male rats weighing 200-240 g. CRF was modeled by unilateral nephrectomy and resection of both poles of the remaining kidney, which reduced the mass of the functioning parenchyma by 80%. In the 1-st series of experiments no therapy was performed. In the 2-nd - 4-th series the animals were intraperitoneally injected with a fractionated xenogenic proteomic complex (secretom) from pig brain stem and progenitor cells (SSPC) at a daily dose of 0.1 ml in different modes: two 10-days courses with a 10-days break between them (2nd series); prolongation of the 1st course up to 20 days and a repeated 10-days course after 10 days (3rd series); continuous SSPC therapy for 30 days (4-th series). 5th series – intact animals. The effectiveness of therapy was evaluated based on the severity of the development of compensatory renal hypertrophy, the dynamics of biochemical parameters of kidney function, the activity of enzymes (ALT, AST, LDH, alkaline phosphatase) in blood and urine and the level of uremic neurotoxins 3-indoxyl sulfate and ptolyl sulfate in the blood. Results. SSPC therapy in all variants contributed to a more pronounced compensatory hypertrophy of the remaining kidney, as well as a decrease in the severity of the main functional indicators after 30 and 60 days: the severity of polyuria decreased, the concentration of urea in the blood decreased to a greater extent, and the glomerular filtration rate and tubular reabsorption of sodium and calcium approached normal values, which was not observed in the control series. The severity of the therapeutic effect was more pronounced with continuous 30-day therapy. There was also a less pronounced increase in the activity of enzymes in the blood and their excretion in the urine, which indicated the cytoprotective effect of SSPC therapy. If in the control series of experiments, the deterioration of the studied indicators were noted with an increase in the observation period from 30 to 60 days, whereas in all experimental series they remained at a subnormal level. SSPC therapy also contributed to a lower accumulation of uremic toxins (3-indoxyl sulfate and p-tolyl sulfate) in the blood. Conclusion. Prolonged therapy of SSPC prevents the progression of CRF by stimulating compensatory hypertrophy of the kidney and cytoprotective effect and promotes more effective elimination of uremic toxins, preventing their accumulation in the blood.

SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria, and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

Exploring the Interactive Role of Parathyroid Hormone and Sodium Intake in Inducing Cardiac Hypertrophy in Rats: A Novel Study.

Background and objectives Previous research has suggested that hyperparathyroidism and excessive salt intake may contribute to the development of cardiac hypertrophy. This study aimed to investigate the relationship and underlying mechanisms between parathyroid hormone (PTH) and salt intake in the development of left ventricular hypertrophy (LVH). Additionally, the study sought to determine whether captopril intervention could reduce the impact of sustained PTH stimulation and excessive salt intake on LVH. Methodology We employed 40 eight-week-old male Sprague-Dawley rats, which were randomly assigned to eight groups: a sham group, a PTH group, a low-salt group (0.6% NaCl), a high-salt group (8% NaCl), a PTH + low-salt group, a PTH + high-salt group, a PTH + low salt + captopril group, and a PTH + high salt + captopril group. The rats were continuously infused with recombinant PTH (1-34) (2 pmol/kg per hour) via an osmotic pump for two weeks and were administered varying concentrations of saline for gavage over two weeks, according to their group. We monitored changes in blood pressure, measured heart weight, left ventricular wall thickness, and myocardial histological morphology, and assessed the relative expression of type III collagen. Results The PTH + high-salt group displayed a significant increase in blood pressure, heart weight, and left ventricular posterior wall thickness (P＜0.05), in addition to myocardial cell hypertrophy and increased Col III expression (P＜0.05), compared to other groups. Captopril intervention significantly reduced blood pressure (P＜0.05), ameliorated myocardial tissue morphology changes, and significantly decreased Col III expression (P＜0.05) but did not entirely reverse the increase in heart weight and left ventricular posterior wall thickness (P＞0.05). Conclusions Our findings suggest that the co-intervention of PTH and high salt can lead to an increase in blood pressure, heart weight, myocardial cell hypertrophy, LVH, and myocardial fibrosis levels in Sprague-Dawley rats. Captopril intervention can lower blood pressure and alleviate pathological myocardial tissue changes and myocardial fibrosis but cannot completely reverse LVH.

White-throated Sparrow (Zonotrichia albicollis) liver and pectoralis flight muscle transcriptomic changes in preparation for migration.

Migratory songbirds undertake challenging journeys to reach their breeding grounds each spring. They accomplish these non-stop flapping feats of endurance through a suite of physiological changes, including the development of substantial fat stores and flight muscle hypertrophy and an increased capacity for fat catabolism. Additionally, migratory birds may show large reductions in organ masses during flight, including the flight muscle and liver, which they must rapidly rebuild during their migratory stopover prior to replenishing their fat stores. However, the molecular basis of this capacity for rapid tissue remodeling and energetic output has not been thoroughly investigated. We performed RNA-seq analysis of the liver and pectoralis flight muscle of captive White-throated Sparrows in the migratory and non-migratory condition to explore the mechanisms of seasonal change to metabolism and tissue mass regulation that may facilitate these migratory journeys. We identified transcriptional alterations to glucose and fatty acid metabolism as well as the production and metabolism of ketone bodies. Based on transcriptional changes, we propose that tissue-specific adjustments in preparation for migration may alleviate the damaging effects of long-duration activity, including a potential increase to the inflammatory response in the muscle. Furthermore, based on transcriptional changes, we hypothesize that seasonal hypertrophy balances satellite cell recruitment and apoptosis, while little evidence appeared in the transcriptome to support MSTN, IGF1, and mTOR-mediated pathways for muscle growth. These findings can encourage more targeted molecular studies on the unique integration of pathways that we find in the development of the migratory endurance phenotype in songbirds.

A machine learning-based score for precise echocardiographic assessment of cardiac remodelling in hypertensive young adults.

Accurate staging of hypertension-related cardiac changes, before the development of significant left ventricular hypertrophy, could help guide early prevention advice. We evaluated whether a novel semi-supervised machine learning approach could generate a clinically meaningful summary score of cardiac remodelling in hypertension. A contrastive trajectories inference approach was applied to data collected from three UK studies of young adults. Low-dimensional variance was identified in 66 echocardiography variables from participants with hypertension (systolic ≥160 mmHg) relative to a normotensive group (systolic < 120 mmHg) using a contrasted principal component analysis. A minimum spanning tree was constructed to derive a normalized score for each individual reflecting extent of cardiac remodelling between zero (health) and one (disease). Model stability and clinical interpretability were evaluated as well as modifiability in response to a 16-week exercise intervention. A total of 411 young adults (29 ± 6 years) were included in the analysis, and, after contrastive dimensionality reduction, 21 variables characterized >80% of data variance. Repeated scores for an individual in cross-validation were stable (root mean squared deviation = 0.1 ± 0.002) with good differentiation of normotensive and hypertensive individuals (area under the receiver operating characteristics 0.98). The derived score followed expected hypertension-related patterns in individual cardiac parameters at baseline and reduced after exercise, proportional to intervention compliance (P = 0.04) and improvement in ventilatory threshold (P = 0.01). A quantitative score that summarizes hypertension-related cardiac remodelling in young adults can be generated from a computational model. This score might allow more personalized early prevention advice, but further evaluation of clinical applicability is required.

An updated review on cell signaling pathways regulated by candidate miRNAs in coronary artery disease

MicroRNAs (miRNAs) are small endogenous non-coding RNA, size range from 17 to 25 nucleotides that regulate gene expression at the post-transcriptional level. More than 2000 different types of miRNAs have been identified in humans which regulate about 60% of gene expression, since the discovery of the first miRNA in 1993. MicroRNA performs many functions such as being involved in the regulation of various biological pathways for example cell migration, cell proliferation, cell differentiation, disease progression, and initiation. miRNAs also play an important role in the development of atherosclerosis lesions, cardiac fibroblast, cardiac hypertrophy, cancer, and neurological disorders. Abnormal activation of many cell signaling pathways has been observed in the development of coronary artery disease. Abnormal expression of these candidate miRNA genes leads to up or downregulation of specific genes, these specific genes play an important role in the regulation of cell signaling pathways involved in coronary artery disease. Many studies have found that miRNAs play a key role in the regulation of crucial signaling pathways that are involved in the pathophysiology of coronary artery disease. This review is designed to investigate the role of cell signaling pathways regulated by candidate miRNAs in Coronary artery disease.

UGCG modulates heart hypertrophy through B4GalT5-mediated mitochondrial oxidative stress and the ERK signaling pathway

Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy.

A new FGF15/19-mediated gut-to-heart axis controls cardiac hypertrophy.

FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway.

Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. Methods and Results Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor-associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation-induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA-seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine-treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B-dependent manner. Conclusions Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.

Effect of diminazene on cardiac hypertrophy through mitophagy in rat models with hyperthyroidism induced by levothyroxine.

Hyperthyroidism is associated with the alteration in molecular pathways involved in the regulation of mitochondrial mass and apoptosis, which contribute to the development of cardiac hypertrophy. Diminazene (DIZE) is an animal anti-infection drug that has shown promising effects on improving cardiovascular disease. The aim of the present study was to investigate the therapeutic effect of DIZE on cardiac hypertrophy and the signaling pathways involved in this process in the hyperthyroid rat model. Twenty male Wistar rats were equally divided into four groups: control, hyperthyroid, DIZE, and hyperthyroid + DIZE. After 28 days of treatment, serum thyroxine (T4) and thyroid stimulating hormone (TSH) level, cardiac hypertrophy indices, cardiac damage markers, cardiac malondialdehyde (MDA), and superoxide dismutase (SOD) level, the mRNA expression level of mitochondrial and apoptotic genes were evaluated. Hyperthyroidism significantly decreased the cardiac expression level of SIRT1/PGC1α and its downstream involved in the regulation of mitochondrial biogenesis, mitophagy, and antioxidant enzyme activities including TFAM, PINK1/MFN2, Drp1, and Nrf2, respectively, as well as stimulated mitochondrial-dependent apoptosis by reducing Bcl-2 expression and increasing Bax expression. Treatment with DIZE significantly reversed the downregulation of SIRT1, PGC1α, PINK1, MFN2, Drp1, and Nrf2 but did not significantly change the TFAM expression. Moreover, DIZE suppressed apoptosis by normalizing the cardiac expression levels of Bax and Bcl-2. DIZE is effective in attenuating hyperthyroidism-induced cardiac hypertrophy by modulating the mitophagy-related pathway, suppressing apoptosis and oxidative stress.

Exploring the Intricate Links between Adenotonsillar Hypertrophy, Mouth Breathing, and Craniofacial Development in Children with Sleep-Disordered Breathing: Unraveling the Vicious Cycle.

Adenotonsillar hypertrophy has been well-acknowledged as the primary instigator of sleep-disordered breathing in the pediatric population. This condition spans a spectrum, from typical age-related growth that the immune system influences to persistent pathological hypertrophy. Reduction in air spaces, metabolic changes, neurobehavioral alterations, and chronic inflammation characterizes the latter form. As the go-to treatment, adenotonsillectomy has proven effective. However, it is not a guarantee for all patients, leaving us without reliable predictors of treatment success. Evidence suggests a connection between adenotonsillar hypertrophy and specific oral breathing patterns resulting from craniofacial development. This finding implies an intricate interdependence between the two, hinting at a self-sustaining vicious cycle that persists without proper intervention. The theories regarding the relationship between craniofacial conformation and sleep-disordered breathing have given rise to intriguing perspectives. In particular, the "gracilization theory" and the "gravitational hypothesis" have provided fascinating insights into the complex interaction between craniofacial conformation and SDB. Further investigation is crucial to unraveling the underlying pathophysiological mechanisms behind this relationship. It is also vital to explore the risk factors linked to adenotonsillectomy failure, study the long-term effects of adenotonsillar hypertrophy on craniofacial growth, and devise innovative diagnostic techniques to detect upper airway compromise early. Moreover, to assess their efficacy, we must delve into novel therapeutic approaches for cases that do not respond to traditional treatment, including positional therapy and orofacial myofunctional therapy. Though complex and unpredictable, these challenges promise to enhance our understanding and treatment of adenotonsillar hypertrophy and its related complications in children. By taking on this task, we can pave the way for more effective and targeted interventions, ultimately improving affected individuals' well-being and quality of life.

Mitochondria and NLRP3 inflammasome in cardiac hypertrophy.

Cardiac hypertrophy is the main adaptive response of the heart to chronic loads; however, prolonged or excessive hypertrophy promotes myocardial interstitial fibrosis, systolic dysfunction, and cardiomyocyte death, especially aseptic inflammation mediated by NLRP3 inflammasome, which can aggravate ventricular remodeling and myocardial damage, which is an important mechanism for the progression of heart failure. Various cardiac overloads can cause mitochondrial damage. In recent years, the mitochondria have been demonstrated to be involved in the inflammatory response during the development of cardiac hypertrophy in vitro and in vivo. As the NLRP3 inflammasome and mitochondria are regulators of inflammation and cardiac hypertrophy, we explored the potential functions of the NLRP3 inflammasome and mitochondrial dysfunction in cardiac hypertrophy. In particular, we proposed that the induction of mitochondrial dysfunction in cardiomyocytes may promote NLRP3-dependent inflammation during myocardial hypertrophy. Further in-depth studies could prompt valuable discoveries regarding the underlying molecular mechanisms of cardiac hypertrophy, reveal novel anti-inflammatory therapies for cardiac hypertrophy, and provide more desirable therapeutic outcomes for patients with cardiac hypertrophy.

Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension

BackgroundA dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes.MethodsTwo-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway.ResultsThe TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway.ConclusionsWe demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.

A diet containing cod backbone proteins attenuated the development of mesangial sclerosis and tubular dysfunction in male obese BTBR ob/ob mice

PurposeThe obese black and tan, brachyuric (BTBR) ob/ob mouse spontaneously develops features comparable to human diabetic nephropathy. The primary aim of the present study was to investigate if a diet containing fish proteins would attenuate or delay the development of glomerular hypertrophy (glomerulomegaly), mesangial sclerosis and albuminuria in obese BTBR ob/ob mice.MethodsObese BTBR.CgLepob/WiscJ male mice were fed diets containing 25% of protein from Atlantic cod backbones and 75% of protein from casein (Cod-BB group), or casein as the sole protein source (control group). Kidneys were analysed morphologically, and markers for renal dysfunction were analysed biochemically in urine and serum.ResultsThe Cod-BB diet attenuated the development of mesangial sclerosis (P 0.040) without affecting the development of glomerular hypertrophy and albuminuria. The urine concentration of cystatin C (relative to creatinine) was lower in mice fed the Cod-BB diet (P 0.0044).ConclusionA diet containing cod backbone protein powder attenuated the development of mesangial sclerosis and tubular dysfunction in obese BTBR ob/ob mice, but did not prevent the development of glomerular hypertrophy and albuminuria in these mice.

Abstract P1139: Remodeling Chromatin Structure To Induce And Reverse Heart Failure

Heart failure is a critical health issue that causes one in nine deaths in the United States. Despite extensive research on gene expression dynamics in the failing myocardium, the mechanisms by which the genome reorganizes itself to reconfigure transcription are poorly understood. CTCF is a crucial protein in chromatin architecture that mediates chromatin looping, acts as an enhancer insulator, and can function as either an activator or repressor of transcription. Our previous research indicates that CTCF plays a crucial role in heart failure, as cardiac-specific knockout of this protein promotes genome organization defects that result in cardiac pathology marked by reduced ejection fraction. To determine whether restoring CTCF levels could reverse this phenotype, we designed an AAV9 vector in which the cardiomyocyte-specific Troponin T promoter drives the expression of CTCF and GFP. Our results show that reintroduction of CTCF into failing CTCF-depleted mouse hearts successfully rescues the pathological phenotype of the animals, characterized by sustained improvement in ejection fraction and left ventricular chamber size in both systole and diastole. Furthermore, RNA-seq experiments reveal numerous differentially expressed genes with opposite transcriptional behavior depending on CTCF levels, including genes involved in chromatin organization (e.g., CHmgb2, Brca1, Smyd2), development of hypertrophy (e.g., Mef2a, Gata4, Mybpc3), extracellular matrix organization (e.g., Adamts5, Itgb1, Vtn) and collagen deposition (e.g., Col5a1, Col5a3). We also examined chromatin architecture through Hi-C experiments and discovered that restoration of CTCF levels remodels the global architecture of chromatin to closely resemble healthy myocyte chromatin. This finding supports the hypothesis that rescue of CTCF levels ameliorates cardiac disease by reverting the observed pathological gene expression profile through genomic reorganization. In summary, our project highlights the crucial role of CTCF in heart failure and demonstrates that structural repair of chromatin organization through modulation of CTCF levels is a novel and realistic approach to treating heart failure.