bims-hafaim 2021-12-05 papers

Issue of 2021–12–05
eight papers selected by
Kyle McCommis, Saint Louis University

Acta Pharmacol Sin. 2021 Dec 01.

Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.

Fang-Fang Ren, Zuo-Yi Xie, Yi-Na Jiang, Xuan Guan, Qiao-Ying Chen, Teng-Fang Lai, Lei Li.

Endoplasmic reticulum stress-mediated apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved caspase 3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 inhibitor EX527 (10 μM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.

Keywords: DAPA; SIRT1; endoplasmic reticulum stress; heart failure; ventricular remodeling

DOI: https://doi.org/10.1038/s41401-021-00805-2

Int J Mol Med. 2022 Jan;pii: 11. [Epub ahead of print]49(1):

EGCG prevents pressure overload‑induced myocardial remodeling by downregulating overexpression of HDAC5 in mice.

Xiao Han, Chang Peng, Lixin Huang, Xiaomei Luo, Qian Mao, Shuqi Wu, Huanting Zhang.

Myocardial remodeling is a complex pathological process and its mechanism is unclear. The present study investigated whether epigallocatechin gallate (EGCG) prevents myocardial remodeling by regulating histone acetylation and explored the mechanisms underlying this effect in the heart of a mouse model of transverse aortic constriction (TAC). A TAC mouse model was created by partial thoracic aortic banding (TAB). Subsequently, TAC mice were injected with EGCG at a dose of 50 mg/kg/day for 12 weeks. The hearts of mice were collected for analysis 4, 8 and 12 weeks after TAC. Histopathological changes in the heart were observed by hematoxylin and eosin, Masson trichrome and wheat germ agglutinin staining. Protein expression levels were investigated using western blotting. Cardiac function of mice was detected by echocardiography. The level of histone acetylated lysine 27 on histone H3 (H3K27ac) first increased and then decreased in the hearts of mice at 4, 8 and 12 weeks after TAC. The expression levels of two genes associated with pathological myocardial remodeling, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), also increased initially but then decreased. The expression levels of histone deacetylase 5 (HDAC5) gradually increased in the hearts of mice at 4, 8 and 12 weeks after TAC. Furthermore, EGCG increased acetylation of H3K27ac by inhibiting HDAC5 in the heart of TAC mice treated with EGCG for 12 weeks. EGCG normalized the transcriptional activity of heart nuclear transcription factor myocyte enhancer factor 2A in TAC mice treated for 12 weeks. The low expression levels of myocardial remodeling‑associated genes (ANP and BNP) were reversed by EGCG treatment for 12 weeks in TAC mice. In addition, EGCG reversed cardiac enlargement and improved cardiac function and survival in TAC mice when treated with EGCG for 12 weeks. Modification of the HDAC5‑mediated imbalance in histone H3K27ac served a key role in pathological myocardial remodeling. The present results show that EGCG prevented and delayed myocardial remodeling in TAC mice by inhibiting HDAC5.

Keywords: EGCG; HDAC; histone acetylation; mice; myocardial remodeling; treatment

DOI: https://doi.org/10.3892/ijmm.2021.5066

Front Physiol. 2021 ;12 785799

Sleeve Gastrectomy Ameliorates Diabetes-Induced Cardiac Hypertrophy Correlates With the MAPK Signaling Pathway.

Qian Xu, Huanxin Ding, Songhan Li, Shuohui Dong, Linchuan Li, Bowen Shi, Mingwei Zhong, Guangyong Zhang.

Background: Cardiac hypertrophy as a main pathological manifestation of diabetic cardiomyopathy (DCM), is a significant complication of diabetes. Bariatric surgery has been proven to relieve DCM; however, whether it can alleviate diabetes-induced cardiac hypertrophy is undefined. Methods: Diabetic and obese rats were performed sleeve gastrectomy (SG) after having diabetes for 16weeks. The rats were euthanized 8weeks after SG. Metabolic parameters, heart function parameters, myocardial glucose uptake, morphometric and histological changes, and the expression level of mitogen-activated protein kinases (MAPKs) were determined and compared among the control group (CON group), diabetes mellitus group (DM group), sham operation group (SHAM group), and SG group. Results: Compared with the SHAM group, the blood glucose, body weight, insulin resistance, and other metabolic parameters were significantly improved in the SG group. There was also a marked improvement in myocardial morphometric and histological parameters after SG. Furthermore, the myocardial glucose uptake and heart function were reversed after SG. Additionally, the phosphorylation of MAPKs was inhibited after SG, including p38 MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases 1/2 (ERK1/2). The expression of DUSP6, which dephosphorylates ERK1/2, was upregulated after SG. These findings suggest that SG ameliorated diabetes-induced cardiac hypertrophy correlates with the MAPK signaling pathway. Conclusion: These results showed that diabetes-induced cardiac hypertrophy was ameliorated after SG was closely related to the inhibition of the MAPK signaling pathway and upregulation of DUSP6. Therefore, this study provides a novel strategy for treating diabetes-induced cardiac hypertrophy.

Keywords: DUSP6; ERK1/2; MAPK; diabetes-induced cardiac hypertrophy; sleeve gastrectomy

DOI: https://doi.org/10.3389/fphys.2021.785799

Circulation. 2021 Nov 30. 144(22): 1795-1817

NAD+ Metabolism in Cardiac Health, Aging, and Disease.

Mahmoud Abdellatif, Simon Sedej, Guido Kroemer.

Nicotinamide adenine dinucleotide (NAD+) is a central metabolite involved in energy and redox homeostasis as well as in DNA repair and protein deacetylation reactions. Pharmacological or genetic inhibition of NAD+-degrading enzymes, external supplementation of NAD+ precursors, and transgenic overexpression of NAD+-generating enzymes have wide positive effects on metabolic health and age-associated diseases. NAD+ pools tend to decline with normal aging, obesity, and hypertension, which are all major risk factors for cardiovascular disease, and NAD+ replenishment extends healthspan, avoids metabolic syndrome, and reduces blood pressure in preclinical models. In addition, experimental elevation of NAD+ improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, or dilated cardiomyopathies, as well as different modalities of heart failure. Here, we critically discuss cardiomyocyte-specific circuitries of NAD+ metabolism, comparatively evaluate distinct NAD+ precursors for their preclinical efficacy, and raise outstanding questions on the optimal design of clinical trials in which NAD+ replenishment or supraphysiological NAD+ elevations are assessed for the prevention or treatment of major cardiac diseases. We surmise that patients with hitherto intractable cardiac diseases such as heart failure with preserved ejection fraction may profit from the administration of NAD+ precursors. The development of such NAD+-centered treatments will rely on technological and conceptual progress on the fine regulation of NAD+ metabolism.

Keywords: NAD; cardiomyopathy; heart failure; human; nicotinamide; nicotinamide mononucleotide; obesity

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.056589

J Cardiovasc Transl Res. 2021 Dec 02.

Dapagliflozin Improves Cardiac Function, Remodeling, Myocardial Apoptosis, and Inflammatory Cytokines in Mice with Myocardial Infarction.

Kai Wang, Zhongming Li, Yan Sun, Xianling Liu, Wenjie Ma, Yinzhang Ding, Jian Hong, Lijun Qian, Di Xu.

Dapagliflozin (DAPA) exerts cardioprotective effects in non-diabetic patients. Nonetheless, the protective mechanism remains unknown. This study aims to evaluate the performance of DAPA on cardiac function and remodeling as well as its potential mechanism in mice with myocardial infarction (MI). Here, a MI mice model was established. One week after MI, mice were treated with saline or DAPA (1.5 mg/kg/day) for 4 weeks. At the end of this study, echocardiography was performed to assess cardiac structure and function. Myocardial apoptosis was analyzed by Western blot and immunofluorescence. Inflammatory cytokines and cardiac fibrosis were analyzed by real-time PCR and Masson's trichrome stain, respectively. Results showed that DAPA improved cardiac structure and function, attenuated cardiac fibrosis, and inhibited inflammatory cytokines and myocardial apoptosis. Moreover, the inhibition of PI3K/AKT/mTOR pathway might be related to the cardioprotective role of DAPA. These findings reveal that dapagliflozin is a potential therapeutic agent for MI patients without diabetes.

Keywords: Cardiac function; Cardiac remodeling; Dapagliflozin; Inflammatory cytokines; Myocardial apoptosis; Myocardial infarction; PI3K/AKT/mTOR signaling pathway

DOI: https://doi.org/10.1007/s12265-021-10192-y

Front Cardiovasc Med. 2021 ;8 734364

Stable Isotopes for Tracing Cardiac Metabolism in Diseases.

Anja Karlstaedt.

Although metabolic remodeling during cardiovascular diseases has been well-recognized for decades, the recent development of analytical platforms and mathematical tools has driven the emergence of assessing cardiac metabolism using tracers. Metabolism is a critical component of cellular functions and adaptation to stress. The pathogenesis of cardiovascular disease involves metabolic adaptation to maintain cardiac contractile function even in advanced disease stages. Stable-isotope tracer measurements are a powerful tool for measuring flux distributions at the whole organism level and assessing metabolic changes at a systems level in vivo. The goal of this review is to summarize techniques and concepts for in vivo or ex vivo stable isotope labeling in cardiovascular research, to highlight mathematical concepts and their limitations, to describe analytical methods at the tissue and single-cell level, and to discuss opportunities to leverage metabolic models to address important mechanistic questions relevant to all patients with cardiovascular disease.

Keywords: cardiovascular disease; metabolic flux analysis; metabolism; stable-isotope tracer; systems biology

DOI: https://doi.org/10.3389/fcvm.2021.734364

Lancet Diabetes Endocrinol. 2021 Nov 30. pii: S2213-8587(21)00292-8. [Epub ahead of print]

Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial.

EMPEROR-Reduced trial committees and investigators

BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies.
METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977.
FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; pinteraction=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; pinteraction=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; pinteraction=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups.
INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy.
FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

DOI: https://doi.org/10.1016/S2213-8587(21)00292-8