The value of computed tomography angiography for evaluation of left atrial enlargement in patients with persistent atrial fibrillation.

BACKGROUND: The post-processing technology of CTA offers significant advantages in evaluating left atrial enlargement (LAE) in patients with persistent atrial fibrillation (PAF). This study aims to identify parameters for rapidly and accurately diagnosing LAE in patients with PAF using CT cross-sections. METHODS: Left atrial pulmonary venous (PV) CT was performed to 300 PAF patients with dual-source CT, and left atrial volume (LAV), left atrial anteroposterior diameter (LAD1), left atrial transverse diameter (LAD2), and left atrial area (LAA) were measured in the ventricular end systolic (ES) and middle diastolic (MD). LA index (LAI) = LA parameter/body surface area (BSA). Left atrial volume index (LAVIES) > 77.7 ml/m2 was used as the reference standard for the LAE diagnosis. RESULTS: 227 patients were enrolled in the group, 101 (44.5%) of whom had LAE. LAVES and LAVMD (r = 0.983), LAVIES and LAVIMD (r = 0.984), LAAES and LAVIES (r = 0.817), LAAMD and LAVIES (r = 0.814) had strong positive correlations. The area under curve (AUC) showed that all measured parameters were suitable for diagnosing LAE, and the diagnostic efficacy was compared as follows: LAA/LAAI> LAD> the relative value index of LAD, LAD2> LAD1. LAA and LAAI demonstrated comparable diagnostic efficacy, with LAA being more readily available than LAAI. CONCLUSIONS: The axial LAA measured by CTA can be served as a parameter for the rapid and accurate diagnosis of LAE in patients with PAF.

Roles of small GTPases in cardiac hypertrophy (Review).

Cardiac hypertrophy results from the heart reacting and adapting to various pathological stimuli and its persistent development is a major contributing factor to heart failure. However, the molecular mechanisms of cardiac hypertrophy remain unclear. Small GTPases in the Ras, Rho, Rab, Arf and Ran subfamilies exhibit GTPase activity and play crucial roles in regulating various cellular responses. Previous studies have shown that Ras, Rho and Rab are closely linked to cardiac hypertrophy and that their overexpression can induce cardiac hypertrophy. Here, we review the functions of small GTPases in cardiac hypertrophy and provide additional insights and references for the prevention and treatment of cardiac hypertrophy.

Loss of cardiomyocyte-specific adhesion G-protein-coupled receptor G1 (ADGRG1/GPR56) promotes pressure overload-induced heart failure.

Adhesion G-protein-coupled receptors (AGPCRs), containing large N-terminal ligand-binding domains for environmental mechano-sensing, have been increasingly recognized to play important roles in numerous physiologic and pathologic processes. However, their impact on the heart, which undergoes dynamic mechanical alterations in healthy and failing states, remains understudied. ADGRG1 (formerly known as GPR56) is widely expressed, including in skeletal muscle where it was previously shown to mediate mechanical overload-induced muscle hypertrophy; thus, we hypothesized that it could impact the development of cardiac dysfunction and remodeling in response to pressure overload. In this study, we generated a cardiomyocyte (CM)-specific ADGRG1 knockout mouse model, which, although not initially displaying features of cardiac dysfunction, does develop increased systolic and diastolic LV volumes and internal diameters over time. Notably, when challenged with chronic pressure overload, CM-specific ADGRG1 deletion accelerates cardiac dysfunction, concurrent with blunted CM hypertrophy, enhanced cardiac inflammation and increased mortality, suggesting that ADGRG1 plays an important role in the early adaptation to chronic cardiac stress. Altogether, the present study provides an important proof-of-concept that targeting CM-expressed AGPCRs may offer a new avenue for regulating the development of heart failure.

Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.

BACKGROUND: Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8 [neural precursor cell expressed developmentally downregulated protein 8]-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy. METHODS: Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. Tandem mass tag (TMT)-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 (lysine residue at site 238) crotonylation. RESULTS: The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy. CONCLUSIONS: Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardiac hypertrophy through GSN neddylation, which provides potential novel therapeutic targets for pathological hypertrophy and cardiac remodeling.

METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5.

Background: Pathological cardiac hypertrophy, a condition that contributes to heart failure, is characterized by its intricate pathogenesis. The meticulous regulation of protein function, localization, and degradation is a crucial role played by deubiquitinating enzymes in cardiac pathophysiology. This study clarifies the participation and molecular mechanism of OTUD1 (OTU Deubiquitinase 1) in pathological cardiac hypertrophy. Methods: We generated a cardiac-specific Otud1 knockout mouse line (Otud1-CKO) and adeno-associated virus serotype 9-Otud1 mice to determine the role of Otud1 in cardiac hypertrophy. Its impact on cardiomyocytes enlargement was investigated using the adenovirus. RNA immunoprecipitation was used to validate the specific m6a methyltransferase interacted with OTUD1 transcript. RNA sequencing in conjunction with immunoprecipitation-mass spectrometry analysis was employed to identify the direct targets of OTUD1. A series of depletion mutant plasmids were constructed to detect the interaction domain of OTUD1 and its targets. Results: Ang II-stimulated neonatal rat cardiac myocytes and mice hearts subjected to transverse aortic constriction (TAC) showed increased protein levels of Otud1. Cardiac hypertrophy and dysfunction were less frequent in Otud1-CKO mice during TAC treatment, while Otud1 overexpression worsened cardiac hypertrophy and remodeling. METTL3 mediated m6A modification of OTUD1 transcript promoted mRNA stability and elevated protein expression. In terms of pathogenesis, Otud1 plays a crucial role in cardiac hypertrophy by targeting Pgam5, leading to the robust activation of the Ask1-p38/JNK signal pathway to accelerate cardiac hypertrophy. Significantly, the pro-hypertrophy effects of Otud1 overexpression were largely eliminated when Ask1 knockdown. Conclusion: Our findings confirm that targeting the OTUD1-PGAM5 axis holds significant potential as a therapeutic approach for heart failure associated with pathological hypertrophy.

Cardioprotective effect of Vitamin D on cardiac hypertrophy through improvement of mitophagy and apoptosis in an experimental rat model of levothyroxine -induced hyperthyroidism.

BACKGROUND: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms. METHODS AND RESULTS: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism. CONCLUSIONS: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage.

Pathways to precision medicine: deciphering the secrets of physiological and pathological atrial enlargement.

Cardiac functional, morphological, and histological analysis, coupled with liquid chromatography and mass spectrometry, of two transgenic mouse models with cardiomyocyte-specific overexpression of insulin-like growth factor 1 receptor (IGF1R) or a dominant-negative PI3K mutant (DCM-dnPI3K) revealed distinctive functional and molecular profiles during physiological (driven by IGF1R overexpression) and pathological (driven by dn-PI3K overexpression) atrial remodeling. The current study confirmed previously reported findings, including ventricular dilatation and enhanced systolic function with no evidence of arrhythmia in IGF1R model, as well as ventricular hypertrophy and decreased systolic function with intermittent atrial fibrillation in DCM-dnPI3K model. Novel findings obtained from the left atrial (LA) characterization of female mice revealed that physiological atrial enlargement resulted from increased atrial myocyte size and was associated with preserved atrial function, as determined by maintained LA ejection fraction (EF). The proteomic profile of IGF1R transgenic (Tg) mice was enriched for metabolic remodeling and showed a protein expression pattern similar to that of healthy human atria; on the other hand, pathological atrial enlargement resulted from increased atrial fibrosis with normal myocyte size and was associated with impaired atrial function due to a reduced LA EF. The proteomic profile of DCM-dnPI3K mice was enriched to both metabolic and structural remodeling and showed a protein expression pattern similar to that of human AF atria.

Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice.

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KOb/c) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KOb/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure-volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KOb/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca2+ transients in paced KOb/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KOb/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues.

Apigenin Attenuates Transverse Aortic Constriction-Induced Myocardial Hypertrophy: The Key Role of miR-185-5p/SREBP2-Mediated Autophagy.

Introduction: Apigenin is a natural flavonoid compound with promising potential for the attenuation of myocardial hypertrophy (MH). The compound can also modulate the expression of miR-185-5p that both promote MH and suppress autophagy. The current attempts to explain the anti-MH effect of apigenin by focusing on changes in miR-185-5p-mediated autophagy. Methods: Hypertrophic symptoms were induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using Ang II and then handled with apigenin. Changes in myocardial function and structure and cell viability and surface area were measured. The role of miR-185-5p in the anti-MH function of apigenin was explored by detecting changes in autophagic processes and miR-185-5p/SREBP2 axis. Results: TAC surgery induced weight increase, structure destruction, and collagen deposition in hearts of model rats. Ang II suppresses cardiomyocyte viability and increased cell surface area. All these impairments were attenuated by apigenin and were associated with the restored level of autophagy. At the molecular level, the expression of miR-185-5p was up-regulated by TAC, while the expression of SREBP2 was down-regulated, which was reserved by apigenin both in vivo and in vitro. The induction of miR-185-5p in cardiomyocytes could counteracted the protective effects of apigenin. Discussion: Collectively, the findings outlined in the current study highlighted that apigenin showed anti-MH effects. The effects were related to the inhibition of miR-185-5p and activation of SREBP, which contributed to the increased autophagy.

MiR-495-3p promotes cardiac hypertrophy by targeting Pum2.

Pathological cardiac hypertrophy (CH) may lead to heart failure and sudden death. MicroRNAs (miRNAs) have been documented to play crucial parts in CH. The objective of this research was to discuss the potential along with molecule mechanism of miR-495-3p in CH. In vivo CH model was induced by aortic banding (AB) in rats. Cellular hypertrophy in H9c2 rat cardiomyocytes was stimulated by angiotensin II (Ang II) treatment. Haematoxylin and eosin (HE), echocardiography and immunofluorescence staining were used to examine the alterations in cardiac function. The outcomes showed that miR-495-3p expression was high in rat model as well as in Ang II-stimulated cardiomyocytes. Besides, silenced miR-495-3p attenuated CH both in vitro and in vivo. Mechanically, miR-495-3p bound to pumilio RNA binding family member 2 (Pum2) 3'UTR and silenced its expression. Rescue assays further notarized that Pum2 silence abrogated the inhibitory impacts of miR-495-3p inhibitor on CH. In a word, the present research uncovered that miR-495-3p promoted CH by targeting Pum2. Therefore, miR-495-3p may be a novel therapeutic molecule for this disease.

TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression.

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

The functional role of m6A demethylase ALKBH5 in cardiomyocyte hypertrophy.

Cardiomyocyte hypertrophy is a major outcome of pathological cardiac hypertrophy. The m6A demethylase ALKBH5 is reported to be associated with cardiovascular diseases, whereas the functional role of ALKBH5 in cardiomyocyte hypertrophy remains confused. We engineered Alkbh5 siRNA (siAlkbh5) and Alkbh5 overexpressing plasmid (Alkbh5 OE) to transfect cardiomyocytes. Subsequently, RNA immunoprecipitation (RIP)-qPCR, MeRIP-qPCR analysis and the dual-luciferase reporter assays were applied to elucidate the regulatory mechanism of ALKBH5 on cardiomyocyte hypertrophy. Our study identified ALKBH5 as a new contributor of cardiomyocyte hypertrophy. ALKBH5 showed upregulation in both phenylephrine (PE)-induced cardiomyocyte hypertrophic responses in vitro and transverse aortic constriction (TAC)/high fat diet (HFD)-induced pathological cardiac hypertrophy in vivo. Knockdown or overexpression of ALKBH5 regulated the occurrence of hypertrophic responses, including the increased cardiomyocyte surface areas and elevation of the hypertrophic marker levels, such as brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). Mechanically, we indicated that ALKBH5 activated JAK2/STAT3 signaling pathway and mediated m6A demethylation on Stat3 mRNA, but not Jak2 mRNA, resulting in the phosphorylation and nuclear translocation of STAT3, which enhances the transcription of hypertrophic genes (e.g., Nppa) and ultimately leads to the emergence of cardiomyocytes hypertrophic growth. Our work highlights the functional role of ALKBH5 in regulating the onset of cardiomyocyte hypertrophy and provides a potential target for hypertrophic heart diseases prevention and treatment. ALKBH5 activated JAK2/STAT3 signaling pathway and mediated m6A demethylation on Stat3 mRNA, but not Jak2 mRNA, resulting in the phosphorylation and nuclear translocation of STAT3, which enhances the transcription of hypertrophic genes (e.g., Nppa) and ultimately leads to the emergence of cardiomyocytes hypertrophic growth.

Characterization of ferroptosis-triggered pyroptotic signaling in heart failure.

Pressure overload-induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)-induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1ß, and neutralizing IL-1ß improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

Cardamonin intervenes in myocardial hypertrophy progression by regulating Usp18.

BACKGROUND: Myocardial hypertrophy is a chronic cardiac condition that often occurs from long-term pressure or volumetric load on the heart. Propranolol hydrochloride has been employed in research on hypertension, pheochromocytoma, myocardial infarction, arrhythmias, angina pectoris, and hypertrophic cardiomyopathy. Current treatments for this condition have side effects, such as arrhythmias and myocardial cell death, thus necessitating safer and more effective alternatives. Recently, natural products have gained attention in drug development because of their low toxicity and high efficacy. Cardamonin, a compound derived from Chinese herbal materials, has shown potential in inhibiting oxidative stress and inflammation, which is beneficial for cardiovascular health. Nevertheless, the impact on myocardial hypertrophy and cardiac remodeling is still uncertain METHODS: Approach We employed a transverse aortic constriction (TAC)model to simulate the pathological conditions of myocardial hypertrophy. Mice were administered varying doses of CAR (10 and 40 mg kg-1/d), and cardiac function was assessed using techniques such as echocardiography, qPCR, Masson staining, DHE staining, immunofluorescence, and immunohistochemistry. Propranolol hydrochloride was the positive control for observing the anti-myocardial hypertrophic effects of CAR. RESULTS: Cardamonin significantly reduced TAC-induced myocardial hypertrophy, fibrosis, inflammation, and oxidative stress. High CAR concentrations showed better anti-myocardial remodeling effects. The anti-hypertrophic effect of cardamonin was similar to that of propranolol hydrochloride. Further investigating the mechanism of action revealed that ubiquitin-specific peptidase (USP)18, a deubiquitnating enzyme that regulates various cellular signaling pathways, was a key downstream regulator affected by cardamonin. To confirm this, AAV9-cTNT-Usp18 and Usp18 myocardial-specific knockout mice were generated and treated with TAC. Usp18 downregulation was found to interfere with the protective effects of CAR against myocardial remodeling, whereas its overexpression enhanced these effects. CONCLUSION: This study used propranolol as a positive control and provided the first in-depth exploration of the concentration-dependent effects of cardamonin on myocardial hypertrophy and cardiac remodeling. CAR is a new candidate drug for cardiovascular disease treatment. This comparative study provides evidence for assessing the clinical application potential of new drugs and delves into its mechanisms of action, particularly the interaction with Usp18. Comprehending these mechanisms is beneficial for formulating more targeted future treatment approaches.

Bisphenol S exposure induces cardiac remodeling and aggravates high-fat diet-induced cardiac hypertrophy in mice.

Bisphenol S (BPS) is widely used in the manufacture products and increase the risk of cardiovascular diseases. The effect of the association between obesity and BPS on cardiac outcomes is still unknown. Male C57BL/6 mice were divided into standard chow diet (SC; 15 kJ/g), standard chow diet + BPS (SCB), high-fat diet (HF; 21 kJ/g), and high-fat diet + BPS (HFB). Over 12 weeks, the groups were exposed to BPS through drinking water (dose: 25 µg/kg/day) and/or a HF diet. We evaluated: body mass (BM), total cholesterol, systolic blood pressure (SBP), left ventricle (LV) mass, and cardiac remodeling. In the SCB group, BM, total cholesterol, and SBP increase were augmented in relation to the SC group. In the HF and HFB groups, these parameters were higher than in the SC and SCB groups. Cardiac hypertrophy was evidenced by augmented LV mass and wall thickness, and ANP protein expression in all groups in comparison to the SC group. Only the HFB group had a thicker LV wall than SCB and HF groups, and increased cardiomyocyte area when compared with SC and SCB groups. Concerning cardiac fibrosis, SCB, HF, and HFB groups presented higher interstitial collagen area, TGFß, and α-SMA protein expression than the SC group. Perivascular collagen area was increased only in the HF and HFB groups than SC group. Higher IL-6, TNFα, and CD11c protein expression in all groups than the SC group evidenced inflammation. All groups had elevated CD36 and PPARα protein expression in relation to the SC group, but only HF and HFB groups promoted cardiac steatosis with increased perilipin 5 protein expression than the SC group. BPS exposure alone promoted cardiac remodeling with pathological concentric hypertrophy, fibrosis, and inflammation. Diet-induced remodeling is aggravated when associated with BPS, with marked hypertrophy, alongside fibrosis, inflammation, and lipid accumulation.

Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome.

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.

Baicalin ameliorates angiotensin II-induced cardiac hypertrophy and mitogen-activated protein kinase signaling pathway activation: A target-based network pharmacology approach.

Baicalin, a flavonoid glycoside from Scutellaria baicalensis Georgi., exerts anti-hypertensive effects. The present study aimed to assess the cardioprotective role of baicalin and explore its potential mechanisms. Network pharmacology analysis pointed out a total of 477 potential targets of baicalin were obtained from the PharmMapper and SwissTargetPrediction databases, while 11,280 targets were identified associating with hypertensive heart disease from GeneCards database. Based on the above 382 common targets, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed enrichment in the regulation of cardiac hypertrophy, cardiac contraction, cardiac relaxation, as well as the mitogen-activated protein kinase (MAPK) and other signaling pathways. Moreover, baicalin treatment exhibited the amelioration of increased cardiac index and pathological alterations in angiotensin II (Ang II)-infused C57BL/6 mice. Furthermore, baicalin treatment demonstrated a reduction in cell surface area and a down-regulation of hypertrophy markers (including atrial natriuretic peptide and brain natriuretic peptide) in vivo and in vitro. In addition, baicalin treatment led to a decrease in the expression of phosphorylated c-Jun N-terminal kinase (p-JNK)/JNK, phosphorylated p38 (p-p38)/p38, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK in the cardiac tissues of Ang II-infused mice and Ang II-stimulated H9c2 cells. These findings highlight the cardioprotective effects of baicalin, as it alleviates hypertensive cardiac injury, cardiac hypertrophy, and the activation of the MAPK pathway.

Renal denervation improves mitochondrial oxidative stress and cardiac hypertrophy through inactivating SP1/BACH1-PACS2 signaling.

BACKGROUND: Renal denervation (RDN) has been proved to relieve cardiac hypertrophy; however, its detailed mechanisms remain obscure. This study investigated the detailed protective mechanisms of RDN against cardiac hypertrophy during hypertensive heart failure (HF). METHODS: Male 5-month-old spontaneously hypertension (SHR) rats were used in a HF rat model, and male Wistar-Kyoto (WKY) rats of the same age were used as the baseline control. Myocardial hypertrophy and fibrosis were evaluated by hematoxylin-eosin (HE) staining and Masson staining. The expression of target molecule was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, immunohistochemical and immunofluorescence, respectively. Cardiomyocyte hypertrophy was induced by norepinephrine (NE) in H9c2 cells in vitro and evaluated by brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and α-myosin heavy chain (α-MHC) levels. Oxidative stress was determined by malondialdehyde (MDA) level, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzyme activities. Mitochondrial function was measured by mitochondrial membrane potential, adenosine triphosphate (ATP) production, mitochondrial DNA (mtDNA) number, and mitochondrial complex I-IV activities. Molecular mechanism was assessed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: RDN decreased sympathetic nerve activity, attenuated myocardial hypertrophy and fibrosis, and improved cardiac function in the rat model of HF. In addition, RDN ameliorated mitochondrial oxidative stress in myocardial tissues as evidenced by reducing MDA and mitochondrial reactive oxygen species (ROS) levels, and enhancing SOD and GSH-Px activities. Moreover, phosphofurin acid cluster sorting protein 2 (PACS-2) and broad-complex, tramtrak and bric à brac (BTB) domain and cap'n'collar (CNC) homolog 1 (BACH1) were down-regulated by RDN. In NE-stimulated H9c2 cells, PACS-2 and BACH1 levels were markedly elevated, and knockdown of them could suppress NE-induced oxidative stress, cardiomyocyte hypertrophy, fibrosis, as well as mitochondrial dysfunction. Transforming growth factor beta1(TGFß1)/SMADs signaling pathway was inactivated by RDN in the HF rats, which sequentially inhibited specificity protein 1 (SP1)-mediated transcription of PACS2 and BACH1. CONCLUSION: Collectively, these data demonstrated that RDN improved cardiac hypertrophy and sympathetic nerve activity of HF rats via repressing BACH1 and PACS-2-mediated mitochondrial oxidative stress by inactivating TGF-ß1/SMADs/SP1 pathway, which shed lights on the cardioprotective mechanism of RDN in HF.

Lactate regulates pathological cardiac hypertrophy via histone lactylation modification.

Under the long-term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention and treatment of myocardial hypertrophy. Histone lysine lactylation (HKla) is a novel post-translational modification that connects cellular metabolism with epigenetic regulation. However, the specific role of HKla in pathological cardiac hypertrophy remains unclear. Our study aims to investigate whether HKla modification plays a pathogenic role in the development of cardiac hypertrophy. The results demonstrate significant expression of HKla in cardiomyocytes derived from an animal model of cardiac hypertrophy induced by transverse aortic constriction surgery, and in neonatal mouse cardiomyocytes stimulated by Ang II. Furthermore, research indicates that HKla is influenced by glucose metabolism and lactate generation, exhibiting significant phenotypic variability in response to various environmental stimuli. In vitro experiments reveal that exogenous lactate and glucose can upregulate the expression of HKla and promote cardiac hypertrophy. Conversely, inhibition of lactate production using glycolysis inhibitor (2-DG), LDH inhibitor (oxamate) and LDHA inhibitor (GNE-140) reduces HKla levels and inhibits the development of cardiac hypertrophy. Collectively, these findings establish a pivotal role for H3K18la in pathological cardiac hypertrophy, offering a novel target for the treatment of this condition.