SPOP Is a Key Trigger of Pathological Cardiac Hypertrophy and Heart Failure.

Glucose Metabolism in Cardiac Hypertrophy and Heart Failure.

Propolis, a traditional medicine, has been widely used for a thousand years as an anti-inflammatory and antioxidant drug. The flavonoid fraction is the main active component of propolis, which possesses a wide range of biological activities, including activities related to heart disease. However, the role of the flavonoids extraction from propolis (FP) in heart disease remains unknown. This study shows that FP could attenuate ISO-induced pathological cardiac hypertrophy (PCH) and heart failure in mice. The effect of the two fetal cardiac genes, atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), on PCH was reversed by FP. Echocardiography analysis revealed cardiac ventricular dilation and contractile dysfunction in ISO-treated mice. This finding is consistent with the increased heart weight and cardiac ANF protein levels, massive replacement fibrosis, and myocardial apoptosis. However, pretreatment of mice with FP could attenuate cardiac dysfunction and hypertrophy in vivo. Furthermore, the cardiac protection of FP was suppressed by the pan-PI3K inhibitor wortmannin. FP is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorder, such as fibrosis. The effects may be closely correlated with PI3K/AKT signaling. FP may be clinically used to inhibit PCH progression and heart failure.

Exercise-Induced Long Noncoding RNAs As New Players in Cardiac Hypertrophy.

Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure

Pathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening. A screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin. Among 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro. Our data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.

N6-methyladenosine modification of SPOP relieves ferroptosis and diabetic cardiomyopathy by enhancing ubiquitination of VDAC3

A metabolic shift from fatty acid (FAO) to glucose oxidation (GO) occurs during cardiac hypertrophy (LVH) and heart failure with reduced ejection fraction (HFrEF), which is mediated by PGC-1α and PPARα. While the transcription factor EB (TFEB) regulates the expression of both PPARGC1A/PGC-1α and PPARA/PPARα, its contribution to metabolic remodeling is uncertain. Luciferase assays were performed to verify that TFEB regulates PPARGC1A expression. Cardiomyocyte-specific Tfeb knockout (cKO) and wildtype (WT) male mice were subjected to 27G transverse aortic constriction or sham surgery for 21 and 56 days, respectively, to induce LVH and HFrEF. Echocardiographic, morphological, and histological analyses were performed. Changes in markers of cardiac stress and remodeling, metabolic shift and oxidative phosphorylation were investigated by Western blot analyses, mass spectrometry, qRT-PCR, and citrate synthase and complex II activity measurements. Luciferase assays revealed that TFEB increases PPARGC1A/PGC-1α expression, which was inhibited by class IIa histone deacetylases and derepressed by protein kinase D. At baseline, cKO mice exhibited a reduced cardiac function, elevated stress markers and a decrease in FAO and GO gene expression compared to WT mice. LVH resulted in increased cardiac remodeling and a decreased expression of FAO and GO genes, but a comparable decline in cardiac function in cKO compared to WT mice. In HFrEF, cKO mice showed an improved cardiac function, lower heart weights, smaller myocytes and a reduction in cardiac remodeling compared to WT mice. Proteomic analysis revealed a comparable decrease in FAO- and increase in GO-related proteins in both genotypes. A significant reduction in mitochondrial quality control genes and a decreased citrate synthase and complex II activities was observed in hearts of WT but not cKO HFrEF mice. TFEB affects the baseline expression of metabolic and mitochondrial quality control genes in the heart, but has only minor effects on the metabolic shift in LVH and HFrEF in mice. Deletion of TFEB plays a protective role in HFrEF but does not affect the course of LVH. Further studies are needed to elucidate if TFEB affects the metabolic flux in stressed cardiomyocytes.

ObjectiveQiliqiangxin Capsule (QL) was investigated for its possible role in cardiac hypertrophy in this study. MethodsQL (0.5 mg/mL) was pre-treated in Neonatal Mouse Ventricular Cardiomyocytes (NMVCs) before induction of cardiomyocyte hypertrophy by Angiotensin II (Ang-II). Immunofluorescence staining for α-actinin was conducted to determine cell surface area. Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) of hypertrophy markers were examined. Ang-II infusion was given to stimulate cardiac hypertrophy in mice. The cardiac function of mice was detected by echocardiography, and the pathological status of myocardial tissue was observed. ResultsThe surface of cardiomyocytes was enlarged by Ang-II, and ANP and BNP levels were increased. QL processing could save these changes. miR-382-5p was upregulated in Ang-II-treated NMVCs, and reducing miR-382-5p could further enhance the therapeutic effect of QL while elevating miR-382-5p weakened the protective effect of QL. QL could inhibit miR-382-5p expression to negatively regulate Activated Transcription Factor 3 (ATF3) expression. Enhancing ATF3 expression rescued miR-382-5p upregulation-mediated role in NMVCs. In addition, QL alleviated Ang-II-stimulated cardiac hypertrophy and cardiac dysfunction in mice. ConclusionQL may alleviate cardiac hypertrophy and cardiac dysfunction via the miR-382-5p/ATF3 axis.

Plin5 deficiency exacerbates pressure overload-induced cardiac hypertrophy and heart failure by enhancing myocardial fatty acid oxidation and oxidative stress

Hold Me Tight

Introduction: Pathological cardiac hypertrophy is a major risk factor for heart failure (HF) and a leading cause of morbidity and mortality worldwide. However, the molecular mechanisms underlying pathological cardiac hypertrophy remain unclear. Hypothesis: In the present study, we investigated the possible underlying effects of UBC9 on cardiac hypertrophy and heart failure. Methods: UBC9 was upregulated in samples of human hypertrophic hearts compared to normal controls using RNA sequencing analysis from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo). Real-time polymerase chain reaction (RT-PCR) and western blotting were used to analyze the expression of UBC9 in samples of human hypertrophic hearts and normal controls. Mice with cardiac-specific over-expression and low-expression of UBC9 by intravenous injection of adeno-associated virus 9 (AAV9)-encoding UBC9 under the control of cardiac troponin T (cTnT) promoter were subjected to transverse aortic construction (TAC). Co-immunoprecipitation assays were performed to determine the mechanism by which UBC9 regulates the expression of forkhead box O3 (FOXO3). Results: UBC9 expression increased in the hearts of patients with hypertrophic cardiomyopathy (HCM) and pressure overload-induced mice, as well as in the Neonatal Mouse Cardiomyocytes (NMCMs) treated with phenylephrine (PE). Cardiac cell-specific UBC9 over-expression alleviates cardiac hypertrophy and dysfunction. Cardiac cell-specific UBC9 knockout aggravates cardiac hypertrophy and heart failure. Mechanistically, UBC9 inhibits LIM and cysteine-rich domain 1 (LMCD1) expression by directly binding to forkhead box O3 (FOXO3), a transcription factor of LMCD1, and promoting FOXO3 dephosphorylation and nuclear translocation, independent of SUMOylation. Conclusions: This study provides a new insight that UBC9, as a potential intervention target in cardiac hypertrophy and HF, may contribute to exploring effective therapeutic strategies for pathological cardiac hypertrophy treatment.

AimsCircular RNAs (circRNAs) are involved in gene regulation in a variety of physiological and pathological processes. The present study aimed to investigate the effect of circRNA_000203 on cardiac hypertrophy and the potential mechanisms involved.Methods and resultsCircRNA_000203 was found to be up-regulated in the myocardium of Ang-II-infused mice and in the cytoplasma of Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Enforced expression of circRNA_000203 enhances cell size and expression of atrial natriuretic peptide and β-myosin heavy chain in NMVCs. In vivo, heart function was impaired and cardiac hypertrophy was aggravated in Ang-II-infused myocardium-specific circRNA_000203 transgenic mice (Tg-circ203). Mechanistically, we found that circRNA_000203 could specifically sponge miR-26b-5p, -140-3p in NMVCs. Further, dual-luciferase reporter assay showed that miR-26b-5p, -140-3p could interact with 3′-UTRs of Gata4 gene, and circRNA_000203 could block the above interactions. In addition, Gata4 expression is transcriptionally inhibited by miR-26b-5p, -140-3p mimic in NMVCs but enhanced by over-expression of circRNA_000203 in vitro and in vivo. Functionally, miR-26b-5p, -140-3p, and Gata4 siRNA, could reverse the hypertrophic growth in Ang-II-induced NMVCs, as well as eliminate the pro-hypertrophic effect of circRNA_000203 in NMVCs. Furthermore, we demonstrated that NF-κB signalling mediates the up-regulation of circRNA_000203 in NMVCs exposed to Ang-II treatment.ConclusionsOur data demonstrated that circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p leading to enhanced Gata4 levels.

Pathological cardiac hypertrophy is a process characterized by significant disturbance of protein turnover. Cullin-associated and Neddylation-dissociated 1 (CAND1) acts as a coordinator to modulate substrate protein degradation by promoting the formation of specific cullin-based ubiquitin ligase 3 complex in response to substrate accumulation, which thereby facilitate the maintaining of normal protein homeostasis. Accumulation of calcineurin is critical in the pathogenesis of cardiac hypertrophy and heart failure. However, whether CAND1 titrates the degradation of hypertrophy related protein eg. calcineurin and regulates cardiac hypertrophy remains unknown. Therefore, we aim to explore the role of CAND1 in cardiac hypertrophy and heart failure and the underlying molecular mechanism. Here, we found that the protein level of CAND1 was increased in cardiac tissues from heart failure (HF) patients and TAC mice, whereas the mRNA level did not change. CAND1-KO+ /- aggravated TAC-induced cardiac hypertrophic phenotypes; in contrast, CAND1-Tg attenuated the maladaptive cardiac remodeling. At the molecular level, CAND1 overexpression downregulated, whereas CAND1-KO+ /- or knockdown upregulated calcineurin expression at both in vivo and in vitro conditions. Mechanistically, CAND1 overexpression favored the assembly of Cul1/atrogin1/calcineurin complex and rendered the ubiquitination and degradation of calcineurin. Notably, CAND1 deficiency-induced hypertrophic phenotypes were partially rescued by knockdown of calcineurin, and application of exogenous CAND1 prevented TAC-induced cardiac hypertrophy. Taken together, our findings demonstrate that CAND1 exerts a protective effect against cardiac hypertrophy and heart failure partially by inducing the degradation of calcineurin.

Decision letter: MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation

Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 2+ overload. In this study, we investigated the effects of ranolazine on pressure overload-induced cardiac hypertrophy and heart failure in mice. Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca 2+ release and increased SR Ca 2+ leak. Ranolazine restored aberrant SR Ca 2+ handling induced by pressure overload. Ranolazine also suppressed Na + overload induced in the failing heart, and restored Na + -induced Ca 2+ overload in an sodium-calcium exchanger (NCX)-dependent manner. Ranolazine suppressed the Ca 2+ -dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor-2(MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T-cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER-initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER-initiated cardiomyocyte apoptosis. Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload-induced cardiac hypertrophy and systolic and diastolic function by restoring Na+ and Ca 2+ handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.