bims-hafaim 2024-11-17 papers

Issue of 2024–11–17
eight papers selected by
Kyle McCommis, Saint Louis University

Front Pharmacol. 2024 ;15 1463381

Underlying mechanisms of ketotherapy in heart failure: current evidence for clinical implementations.

Heart failure (HF) is a life-threatening cardiac syndrome characterized by high morbidity and mortality, but current anti-heart failure therapies have limited efficacy, necessitating the urgent development of new treatment drugs. Exogenous ketone supplementation helps prevent heart failure development in HF models, but therapeutic ketosis in failing hearts has not been systematically elucidated, limiting the use of ketones to treat HF. Here, we summarize current evidence supporting ketotherapy in HF, emphasizing ketone metabolism in the failing heart, metabolic and non-metabolic therapeutic effects, and mechanisms of ketotherapy in HF, involving the dynamics within the mitochondria. We also discuss clinical strategies for therapeutic ketosis, aiming to deepen the understanding of the characteristics of ketone metabolism, including mitochondrial involvement, and its clinical therapeutic potential in HF.

Keywords: cardiovascular protection; energy metabolism; heart failure; ketogenic treatment; ketone bodies; mechanisms of ketotherapy

DOI: https://doi.org/10.3389/fphar.2024.1463381

Circulation. 2024 Nov 12. 150(20): 1584-1587

Ketone Treatment in Heart Failure With Preserved Ejection Fraction: Recharging the Heart or Reducing Filling Pressures?

Suzanne N Voorrips, B Daan Westenbrink.

Keywords: Editorials; energy metabolism; exercise tolerance; heart failure, diastolic; ketone bodies

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.071608

Cardiovasc Diabetol. 2024 Nov 07. 23(1): 399

ZIP7 contributes to the pathogenesis of diabetic cardiomyopathy by suppressing mitophagy in mouse hearts.

Ningzhi Yang, Rui Zhang, Hualu Zhang, Yonghao Yu, Zhelong Xu.

BACKGROUND: Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM.
METHODS: T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB.
RESULTS: ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn2+ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn2+ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM.
CONCLUSIONS: ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn2+ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy.

Keywords: Cardiomyopathy; Mitophagy; PINK1/Parkin pathway; T2DM; ZIP7

DOI: https://doi.org/10.1186/s12933-024-02499-2

ESC Heart Fail. 2024 Nov 11.

Dapagliflozin alleviates high-fat-induced obesity cardiomyopathy by inhibiting ferroptosis.

Di Chen, Jiahao Shi, Yue Wu, Lizhu Miao, Zilin Wang, Yixuan Wang, Siwei Xu, Yu Lou.

AIM: Dapagliflozin (Dapa) is a novel hypoglycaemic agent with multiple cardiovascular protective effects, and it is widely used in treatment of heart failure patients, but whether it can improve obese phenotype of heart failure and its mechanism is still unclear. Ferroptosis is an iron dependent form of cell death and has been proved to be an important role in heart failure. The aim of this study is to determine whether Dapa improves obesity-related heart failure by regulating ferroptosis in high-fat diet rats.
METHODS AND RESULTS: Male SD rats were fed a high-fat diet for 12 weeks and confirmed of obese heart failure by metabolic parameters and cardiac ultrasound. Being overweight by 20% compared with the normal group, with elevated systolic blood pressure and abnormal levels of insulin and blood lipid (TG and LDL-c), is recognized as obesity. The obese rats with reduced EF, FS, and E/A shown on ultrasound are defined as the obese heart failure (OHF) group. Histological tests confirmed the more pronounced cardiac fibrosis, mitochondrial volume and collagen deposition in OHF group. Dapa treatment effectively reduced body weight, INS, ISI/IRI index, TG and HDL-C levels (P < 0.05). Also, Dapa administration can slightly decrease the SBP and DBP levels; however, there was no statistical difference among those four groups. Furthermore, Dapa treatment can significantly improve high-fat induced systolic and diastolic dysfunction via regulating cardiac histological abnormalities, including less obvious mitochondrial swelling, muscle fibre dissolution and collagen deposition. Additionally, genes from the OHF group were used by GO enrichment analysis, and it shows that ferroptosis metabolic pathway participated in the development of obese phenotype of heart failure. More importantly, Dapa significantly inhibited Fe2+ and MDA levels (P < 0.05), but augmented GSH content (P < 0.05). In addition, the mRNAs and protein expression of some important regulators of ferroptosis, like GPX4, SLC7A11, FTH1 and FPN1, were all decreased after Dapa intervention.
CONCLUSION: Dapa improved high-fat induced obese cardiac dysfunction via regulating ferroptosis pathway.

Keywords: Dapagliflozin; Ferroptosis; Obesity‐related cardiomyopathy; SGLT2i

DOI: https://doi.org/10.1002/ehf2.15150

ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3279-3298

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.

Linh Thi Truc Pham, Supachoke Mangmool, Warisara Parichatikanond.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

DOI: https://doi.org/10.1021/acsptsci.4c00240

Free Radic Biol Med. 2024 Nov 05. pii: S0891-5849(24)01028-1. [Epub ahead of print]225 856-870

Targeting DUSP26 to drive cardiac mitochondrial dynamics via FAK-ERK signaling in diabetic cardiomyopathy.

Chong Liu, Xiangli Xu, Guiming Sun, Chengchao Song, Shuangquan Jiang, Ping Sun, Jiawei Tian.

Diabetic cardiomyopathy (DCM) is a severe cardiac complication of diabetes mellitus, characterized by structural and functional myocardial abnormalities. The molecular mechanisms underlying DCM, particularly the role of dual-specificity phosphatase 26 (DUSP26), remain insufficiently understood. Our study reveals that DUSP26 expression is markedly downregulated in the cardiomyocytes of diabetic db/db mice and under glucolipotoxic stress. Overexpression of DUSP26 in db/db mice significantly improved cardiac function, as demonstrated by enhanced left ventricular ejection fraction and fractional shortening, alongside reduced myocardial fibrosis and hypertrophy. Mitochondrial analysis indicated that DUSP26 overexpression led to increased ATP production, enhanced mitochondrial fusion, and improved structural integrity. In addition, lipid accumulation was reduced, reflecting enhanced metabolic function. We also discovered that DUSP26 is necessary for regulating the focal adhesion kinase (FAK)-extracellular signal-regulated kinase (ERK) pathway, with pharmacological activation of FAK partially offsetting the benefits of DUSP26 overexpression in rescue experiments. These findings underscore the pivotal role of DUSP26 as a potential therapeutic target, highlighting the importance of developing targeted molecular interventions to address diabetic cardiac complications.

Keywords: Cardiac function; DUSP26; Diabetic cardiomyopathy; FAK-ERK signaling; Mitochondrial dynamics

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.11.006