bims-hafaim 2023-04-09 papers

Issue of 2023–04–09
six papers selected by
Kyle McCommis, Saint Louis University

Diabetol Metab Syndr. 2023 Apr 01. 15(1): 64

Dynamic evolution and mechanism of myocardial glucose metabolism in different functional phenotypes of diabetic cardiomyopathy - a study based on 18 F-FDG microPET myocardial metabolic imaging.

Xiaoliang Shao, Yaqi Liu, Mingge Zhou, Min Xu, Yuqi Chen, Hongbo Huang, Jianguo Lin, Yuetao Wang.

PURPOSE: To use 18 F-FDG microPET dynamic imaging to preliminarily identify the changes of myocardial glucose metabolism corresponding to different functional phenotypes of diabetic cardiomyopathy (DCM) in mice and elucidate their relationships.
METHODS: Left ventricular function was measured by echocardiography in C57BL/KsJ-db/db (db/db) mice and their controls at 8, 12, 16, and 20 weeks of age to divide DCM stages and functional phenotypes. Myocardial histopathology was used to verify the staging accuracy and list-mode microPET dynamic imaging was conducted. The myocardial metabolic rate of glucose (MRglu) and the glucose uptake rate constant (Ki) were derived via Patlak graphical analysis, and the differences in myocardial glucose metabolism levels in different DCM stages were compared. The key proteins involved in myocardial glucose metabolism signaling pathway were analyzed by Western blotting to elucidate the underlying mechanism of abnormal glucose metabolism in DCM.
RESULTS: Compared with the controls, the ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (E/e') of db/db mice was significantly increased from the age of 12 weeks, while the left ventricular ejection fraction (LVEF) was significantly decreased from the age of 16 weeks (all P < 0.05). Based on the staging criteria, 8 and 12 weeks (8/12w) db/db mice were in DCM stage 1 (diastolic dysfunction with normal LVEF), and 16 and 20 weeks (16/20w) db/db mice were in DCM stage 2/3 (diastolic and systolic dysfunction). The degree of myocardial fibrosis, glycogen deposition and ultrastructural damage in 16/20w db/db mice were more obvious than those in 8/12w group. The myocardial MRglu, Ki of db/db mice in 8/12w group or 16/20w group were significantly lower than those in the control group (all P < 0.05), while the myocardial standard uptake value (SUV) was not significantly reduced in the 8/12w group compared with the control group (P > 0.05). MRglu and SUV were moderately negatively correlated with the E/e' ratio (r=-0.539 and - 0.512, P = 0.007 and 0.011), which were not significantly correlated with LVEF (P > 0.05). Meanwhile, Ki was not significantly correlated with LVEF or E/e' ratio. The decreased expression of glucose transporter (GLUT) -4 in db/db mice preceded GLUT-1 and was accompanied by decreased phosphorylated AMP-activated protein kinase (p-AMPK) expression. Myocardial MRglu, Ki and SUV were significantly positively correlated with the expression of GLUT-4 (MRglu: r = 0.537; Ki: r = 0.818; SUV: r = 0.491; P = 0.000 ~ 0.046), but there was no significant correlation with GLUT-1 expression (P = 0.238 ~ 0.780).
CONCLUSIONS: During the progression of DCM, with the changes of left ventricular functional phenotype, abnormal and dynamic changes of myocardial glucose metabolism can occur in the early stage.

Keywords: Cardiac function; Diabetic cardiomyopathy; Mechanism; Myocardial glucose metabolism; microPET

DOI: https://doi.org/10.1186/s13098-023-01038-5

Precis Clin Med. 2023 Mar;6(1): pbad005

Circulating metabolic signatures of heart failure in precision cardiology.

Huijing Xie, Bowen Zhang, Maodi Xie, Tao Li.

Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals. Metabolic remodeling plays a causal role in the pathogenesis of heart failure (HF). Changes in metabolic pathways such as substrate preference, high-energy phosphate metabolism and amino acid metabolism, are involved in pathological structural remodeling and functional impairment. These metabolic alterations are usually not restricted in the cardiac tissue, but also manifest in circulation. In clinical practice, blood sample is routinely used for HF screening. Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation. An increasing number of metabolic biomarkers have been implicated in disease progression, making it possible to fight HF in a more effective and precise way. This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF, aiming to provide new insights into the prevention, diagnosis and treatment of HF in the era of precision medicine.

Keywords: glucose; heart failure; ketone bodies; lipids; metabolomics; precision medicine

DOI: https://doi.org/10.1093/pcmedi/pbad005

Int Immunopharmacol. 2023 Apr 03. pii: S1567-5769(23)00393-4. [Epub ahead of print]118 110072

New insights into the molecular mechanisms of SGLT2 inhibitors on ventricular remodeling.

Yang Chen, Daoquan Peng.

Ventricular remodeling is a pathological process of ventricular response to continuous stimuli such as pressure overload, ischemia or ischemia-reperfusion, which can lead to the change of cardiac structure and function structure, which is central to the pathophysiology of heart failure (HF) and is an established prognostic factor in patients with HF. Sodium glucose cotransporter 2 inhibitors (SGLT2i) get a new hypoglycemic drug that inhibit sodium glucose coconspirator on renal tubular epithelial cells. Recently, clinical trials increasingly and animal experiments increasingly have shown that SGLT2 inhibitors have been largely applied in the fields of cardiovascular diseases, forinstance heart failure, myocardial ischemia-reperfusion injury, myocardial infarction, atrial fibrillation, metabolic diseases such as obesity, diabetes cardiomyopathy and other diseases play a cardiovascular protective role in addition to hypoglycemic. These diseases are association with ventricular remodeling. Inhibiting ventricular remodeling can improve the readmission rate and mortality of patients with heart failure. So far, clinical trials and animal experiments demonstrate that the protective effect of SGLT2 inhibitors in the cardiovascular field is bound to inhibit ventricular remodeling. Therefore, this review briefly investigates the molecular mechanisms of SGLT2 inhibitors on ameliorating ventricular remodeling, and further explore the mechanisms of cardiovascular protection of SGLT2 inhibitors, in order to establish strategies for ventricular remodeling to prevent the progress of heart failure.

Keywords: Heart failure; Molecular mechanisms; SGLT2 inhibitors; Ventricular remodeling

DOI: https://doi.org/10.1016/j.intimp.2023.110072

Exp Mol Med. 2023 Apr 03.

Evogliptin, a DPP-4 inhibitor, prevents diabetic cardiomyopathy by alleviating cardiac lipotoxicity in db/db mice.

Trong Kha Pham, To Hoai T Nguyen, Joo Mi Yi, Gwang Sil Kim, Hyeong Rok Yun, Hyoung Kyu Kim, Jong Chul Won.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.

DOI: https://doi.org/10.1038/s12276-023-00958-6

Front Cardiovasc Med. 2023 ;10 1133611

Roles of histone acetylation sites in cardiac hypertrophy and heart failure.

Masafumi Funamoto, Masaki Imanishi, Koichiro Tsuchiya, Yasumasa Ikeda.

Heart failure results from various physiological and pathological stimuli that lead to cardiac hypertrophy. This pathological process is common in several cardiovascular diseases and ultimately leads to heart failure. The development of cardiac hypertrophy and heart failure involves reprogramming of gene expression, a process that is highly dependent on epigenetic regulation. Histone acetylation is dynamically regulated by cardiac stress. Histone acetyltransferases play an important role in epigenetic remodeling in cardiac hypertrophy and heart failure. The regulation of histone acetyltransferases serves as a bridge between signal transduction and downstream gene reprogramming. Investigating the changes in histone acetyltransferases and histone modification sites in cardiac hypertrophy and heart failure will provide new therapeutic strategies to treat these diseases. This review summarizes the association of histone acetylation sites and histone acetylases with cardiac hypertrophy and heart failure, with emphasis on histone acetylation sites.

Keywords: acetylation; cardiac hypertrophy; epigenetics; heart failure; histone post-translational modification

DOI: https://doi.org/10.3389/fcvm.2023.1133611

Exp Ther Med. 2023 Apr;25(4): 172

4'‑O‑methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway.

Han Sun, Guanghao Zhu, Shuang Ling, Jun Liu, Jin-Wen Xu.

Pathological cardiac hypertrophy is an independent risk factor for complications such as arrhythmia, myocardial infarction, sudden mortality and heart failure. Succinate, an intermediate product of the Krebs cycle, is released into the bloodstream by cells; its levels increase with exacerbations of hypertension, myocardial and other tissue damage and metabolic disease. Succinate may also be involved in several metabolic pathways and mediates numerous pathological effects through its receptor, succinate receptor 1 (SUCNR1; previously known as GPR91). Succinate-induced activation of SUCNR1 has been reported to be related to cardiac hypertrophy, making SUCNR1 a potential target for treating cardiac hypertrophy. Traditional Chinese medicine (TCM) and its active ingredients have served important roles in improving cardiac functions and treating heart failure. The present study investigated whether 4'-O-methylbavachadone (MeBavaC), an active ingredient of the herbal remedy Fructus Psoraleae, which is often used in TCM and has protective effect on myocardial injury and hypertrophy induced by adriamycin, ischemia-reperfusion and sepsis, could ameliorate succinate-induced cardiomyocyte hypertrophy by inhibiting the NFATc4 pathway. Using immunofluorescence staining, reverse transcription-quantitative PCR, western blotting and molecular docking analysis, it was determined that succinate activated the calcineurin/NFATc4 and ERK1/2 pathways to promote cardiomyocyte hypertrophy. MeBavaC inhibited cardiomyocyte hypertrophy, nuclear translocation of NFATc4 and ERK1/2 signaling activation in succinate-induced cardiomyocytes. Molecular docking analysis revealed that MeBavaC interacts with SUCNR1 to form a relatively stable binding and inhibits the succinate-SUCNR1 interaction. The results demonstrated that MeBavaC suppressed cardiomyocyte hypertrophy by blocking SUCNR1 receptor activity and inhibiting NFATc4 and ERK1/2 signaling, which will contribute to the preclinical development of this compound.

Keywords: 4'-O-methylbavachalcone; cardiomyocyte hypertrophy; nuclear factor activated T cell; succinate; succinate receptor 1

DOI: https://doi.org/10.3892/etm.2023.11871