bims-hafaim 2024-12-15 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024–12–15
seven papers selected by
Kyle McCommis, Saint Louis University

Mitochondrial Dysfunction and Calcium Homeostasis in Heart Failure: Exploring the Interplay Between Oxidative Stress and Cardiac Remodeling for Future Therapeutic Innovations.
Central SGLT2 mediate sympathoexcitation in hypertensive heart failure via attenuating subfornical organ endothelial cGAS ubiquitination to amplify neuroinflammation: Molecular mechanism behind sympatholytic effect of Empagliflozin.
GLP-1 Receptor Agonist in Non-obese Patients with Type-2 Diabetes Mellitus and Heart Failure with Preserved Ejection Fraction.
Suppression of cyclooxygenase-2 predisposes to heart failure with preserved ejection fraction.
Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy.
Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model.

Curr Probl Cardiol. 2024 Dec 07. pii: S0146-2806(24)00603-0. [Epub ahead of print] 102968

Mitochondrial Dysfunction and Calcium Homeostasis in Heart Failure: Exploring the Interplay Between Oxidative Stress and Cardiac Remodeling for Future Therapeutic Innovations.

Emily Johnson, Liam Nguyen, Jameela Shukri Albakri, Oliver Smith.

  Heart failure (HF) is a multifaceted clinical syndrome characterized by the heart's inability to pump sufficient blood to meet the body's metabolic demands. It arises from various etiologies, including myocardial injury, hypertension, and valvular heart disease. A critical aspect of HF pathophysiology involves mitochondrial dysfunction, particularly concerning calcium (Ca2+) homeostasis and oxidative stress. This review highlights the pivotal role of excess mitochondrial Ca2+ in exacerbating oxidative stress, contributing significantly to HF progression. Novel insights are provided regarding the mechanisms by which mitochondrial Ca2+ overload leads to increased production of reactive oxygen species (ROS) and impaired cellular function. Despite this understanding, key gaps in research remain, particularly in elucidating the complex interplay between mitochondrial dynamics and oxidative stress across different HF phenotypes. Furthermore, therapeutic strategies targeting mitochondrial dysfunction are still in their infancy, with limited applications in clinical practice. By summarizing recent findings and identifying these critical research gaps, this review aims to pave the way for innovative therapeutic approaches that improve the management of heart failure, ultimately enhancing patient outcomes through targeted interventions.

Keywords:  Calcium Homeostasis; Cardiac Remodeling; Cardiomyocyte Function; Heart Failure; Mitochondrial Ca2+; Mitochondrial Dysfunction; Oxidative Stress

DOI:  https://doi.org/10.1016/j.cpcardiol.2024.102968
Int Immunopharmacol. 2024 Dec 07. pii: S1567-5769(24)02233-1. [Epub ahead of print]145 113711

Central SGLT2 mediate sympathoexcitation in hypertensive heart failure via attenuating subfornical organ endothelial cGAS ubiquitination to amplify neuroinflammation: Molecular mechanism behind sympatholytic effect of Empagliflozin.

Shutian Zhang, Yijun Huang, Chengzhi Han, Fanshun Wang, Maoxiang Chen, Zhaohua Yang, Shouguo Yang, Chunsheng Wang.

   BACKGROUND: Sodium/glucose co-transporter 2 (SGLT2) inhibitors have transformed heart failure (HF) treatment, offering sympatholytic effects whose mechanisms are not fully understood. Our previous studies identified Cyclic GMP-AMP synthase (cGAS)-derived neuroinflammation in the Subfornical organ (SFO) as a promoter of sympathoexcitation, worsening myocardial remodeling in HF. This research explored the role of central SGLT2 in inducing endothelial cGAS-driven neuroinflammation in the SFO during HF and assessed the impact of SGLT2 inhibitors on this process.
METHODS: Hypertensive HF was induced in mice via Angiotensin II infusion for four weeks. SGLT2 expression and localization in the SFO were determined through immunoblotting and double-immunofluorescence staining. AAV9-TIE-shRNA (SGLT2) facilitated targeted SGLT2 knockdown in SFO endothelial cells (ECs), with subsequent analyses via immunoblotting, staining, and co-immunoprecipitation to investigate interactions with cGAS, mitochondrial alterations, and pro-inflammatory pathway activation. Renal sympathetic nerve activity and heart rate variability were measured to assess sympathetic output, alongside evaluations of cardiac function in HF mice.
RESULTS: In HF model mice, SGLT2 levels are markedly raised in SFO ECs, disrupting mitochondrial function and elevating oxidative stress. SGLT2 knockdown preserved mitochondrial integrity and function, reduced inflammation, and highlighted the influence of SGLT2 on mitochondrial health. SGLT2's interaction with cGAS prevented its ubiquitination and degradation, amplifying neuroinflammation and HF progression. Conversely, Empagliflozin counteracted these effects, suggesting that targeting the SGLT2-cGAS interaction as a novel HF treatment avenue.
CONCLUSION: This study revealed that SGLT2 directly reduced cGAS degradation in brain ECs, enhancing neuroinflammation in the SFO, and promoting sympathoexcitation and myocardial remodeling. The significance of the central SGLT2-cGAS interaction in cardiovascular disease mechanisms is emphasized.

Keywords:  Empagliflozin; Heart failure; Neuroinflammation; SGLT2; Subfornical organ; cGAS

DOI:  https://doi.org/10.1016/j.intimp.2024.113711
J Card Fail. 2024 Dec 10. pii: S1071-9164(24)00962-X. [Epub ahead of print]

GLP-1 Receptor Agonist in Non-obese Patients with Type-2 Diabetes Mellitus and Heart Failure with Preserved Ejection Fraction.

Sumanth Khadke, Ashish Kumar, Ammar Bhatti, Sourbha S Dani, Sadeer Al-Kindi, Khurram Nasir, Salim S Virani, Jagriti Upadhyay, Dinamarie C Garcia-Banigan, Sonu Abraham, Raya Husami, Yixin Kong, Sherif Labib, David Venesy, Sachin Shah, Daniel Lenihan, Muthiah Vaduganathan, Anita Deswal, Gregg C Fonarow, Javed Butler, Anju Nohria, Mikhail N Kosiborod, Sarju Ganatra.

   BACKGROUND: Glucagon like peptide-1 receptor agonists (GLP-1RA) promote weight loss and improve heart failure-related symptoms, quality of life, and functional capacity in patients with obesity and heart failure with preserved ejection fraction (HFpEF). However, their clinical effectiveness in non-obese patients with diabetes and HFpEF is understudied.
METHODS: The TriNetX research network was used to identify adult patients (≥18 years) with type 2 diabetes mellitus (T2DM), Heart failure with preserved ejection fraction ((Left ventricular ejection fraction ≥45%), elevated brain natriuretic peptide (≥150pg/mL) or N-terminal pro-B-type natriuretic peptide(≥450pg/mL) and a body mass index (BMI) <30 kg/m2 on or before August 31, 2022. Patients were divided into two groups based on GLP-1RA use. After propensity score matching, Cox proportional Hazard Ratios (HRs) were used to compare outcomes over a 12-month follow-up period.
RESULTS: The study included 84,990 patients (n= 42,495 per group, mean age 64 years, 49% females, 65% white). Patients on GLP-1RA were associated with lower incidence of heart failure exacerbation events (HR 0.60, 95% CI 0.58-0.62, p<0.001) and all-cause emergency room visits or hospitalizations (HR 0.67, 95% CI 0.66-0.69, p<0.001) compared to those not on GLP-1RA. Other outcomes including acute myocardial infarction, atrial fibrillation, ischemic stroke, pulmonary hypertension, C-reactive protein ≥5mg/L, acute kidney injury, and the need for renal replacement therapy, were also significantly less frequent in the GLP-1RA group. These associated benefits persisted even among patients on sodium-glucose cotransporter-2 inhibitors (SGLT2i).
CONCLUSION: GLP-1RA use is associated with improved cardiovascular outcomes in non-obese patients with T2DM and HFpEF and has an associated incremental benefit even among patients on SGLT2i.

Keywords:  GLP-1R agonists; Heart failure with preserved ejection fraction; SGLT 2 inhibitors

DOI:  https://doi.org/10.1016/j.cardfail.2024.10.448
bioRxiv. 2024 Nov 26. pii: 2024.09.28.615616. [Epub ahead of print]

Suppression of cyclooxygenase-2 predisposes to heart failure with preserved ejection fraction.

Emanuela Ricciotti, Philip G Haines, Manu Beerens, Uri Kartoun, Cecilia Castro, Soon Yew Tang, Soumita Ghosh, Ujjalkumar S Das, Nicholas F Lahens, Tao Wang, Jules L Griffin, Stanley Y Shaw, Calum A MacRae, Garret A FitzGerald.

Heart failure (HF) is one of the most strongly associated adverse cardiovascular events linked to the use of cyclooxygenase (COX)-2 selective and non-selective nonsteroidal anti-inflammatory drug (NSAID). Nevertheless, it remains uncertain whether NSAID exposure is more likely to lead to heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). In adult mice, postnatal genetic deletion or pharmacological inhibition of COX-2 did not affect cardiac function. In contrast, aged female inducible COX-2 (iCOX-2) knockout (KO) mice displayed diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and elevated levels of plasma N-terminal pro B-type natriuretic peptide (BNP) when compared to age- and sex- matched controls, while their ejection fraction (EF) remained preserved (≥ 50%). No such phenotype was observed in aged male iCox-2 KO mice. Aged female iCox-2 KO mice showed a shift from prostanoid to leukotriene biosynthesis, along with changes in the expression of mitochondrial genes and calcium-handling proteins in the myocardium. The ratio of phospholamban to SERCA2a was increased, indicating an inhibitory effect on SERCA2a activity, which may contribute to impaired myocardial relaxation. In larval zebrafish, COX-2 inhibition by celecoxib caused a modest yet significant reduction in heart rate and diastolic function, while EF was preserved. Additionally, celecoxib increased BNP expression and ventricular calcium transient amplitude. Diabetic patients in the Harvard-Partners electronic medical record exposed to NSAIDs selective for COX-2 inhibition were more strongly associated with an increased risk of HFpEF compared to HFrEF. Collectively, these findings indicate that COX-2 deletion or inhibition does not impair systolic cardiac function but instead leads to an HFpEF phenotype in mice, zebrafish, and humans. An imbalance in calcium handling may mediate the impairment of myocardial relaxation following COX-2 suppression.
Summary: Genetic deletion or pharmacological inhibition of COX-2 results in heart failure with preserved ejection fraction across zebrafish, mice, and humans.

DOI: https://doi.org/10.1101/2024.09.28.615616
Br J Pharmacol. 2024 Dec 11.

Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy.

Zhenduo Zhu, Qiuyun Guan, Bing Xu, Sherif Bahriz, Ao Shen, Toni M West, Yu Zhang, Bingqing Deng, Wei Wei, Yongsheng Han, Qingtong Wang, Yang K Xiang.

   BACKGROUND AND PURPOSE: Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) is impaired in heart failure. Phosphodiesterases (PDEs) are implicated in the modulation of local cAMP signals and protein kinase A (PKA) activity essential for cardiac function. We characterise PDE isoforms that underlie decreased activities of SERCA2a and reduced cardiac contractile function in diabetic cardiomyopathy.
EXPERIMENTAL APPROACH: Wild type mice were fed with either normal chow or a high-fat diet (HFD). Cardiomyocytes were isolated for excitation-contraction coupling (ECC), fluorescence resonant energy transfer PKA biosensor and proximity ligation assays.
KEY RESULTS: The upregulated PDE4D3 and PDE4D9 isoforms in HFD cardiomyocytes specifically bound to SERCA2a but not ryanodine receptor 2 (RyR2) on the sarcoplasmic reticulum (SR). The increased association of PDE4D isoforms with SERCA2a in HFD cardiomyocytes led to reduced local PKA activities and phosphorylation of phospholamban (PLB) but minimally effected the PKA activities and phosphorylation of RyR2. These changes correlate with slower calcium decay tau in the SR and attenuation of ECC in HFD cardiomyocytes. Selective inhibition of PDE4D3 or PDE4D9 restored PKA activities and phosphorylation of PLB at the SERCA2a complex, recovered calcium decay tau, and increased ECC in HFD cardiomyocytes. Therapies with PDE4 inhibitor roflumilast, PDE4D inhibitor BPN14770 or genetical deletion of PDE4D restored PKA phosphorylation of PLB and cardiac contractile function.
CONCLUSION AND IMPLICATIONS: The current study identifies upregulation of specific PDE4D isoforms that selectively inhibit SERCA2a function in HFD-induced cardiomyopathy, indicating that this remodelling can be targeted to restore cardiac contractility in diabetic cardiomyopathy.

Keywords:  PDE4D; SERCA2a; diabetic cardiomyopathy; excitation contraction coupling; myocytes

DOI:  https://doi.org/10.1111/bph.17411
J Gen Physiol. 2025 Jan 06. pii: e202413583. [Epub ahead of print]157(1):

Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.

Amy D Hanna, Ting Chang, Kevin S Ho, Rachel Sue Zhen Yee, William Cameron Walker, Nadia Agha, Chih-Wei Hsu, Sung Yun Jung, Mary E Dickinson, Md Abul Hassan Samee, Christopher S Ward, Chang Seok Lee, George G Rodney, Susan L Hamilton.

Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in adult hearts compared with control animals. However, only the early embryonic deletion of FKBP12 (αMHC-Cre) resulted in an early-onset and progressive DCM, increased cardiac oxidative stress, altered expression of proteins associated with cardiac remodeling and disease, and sarcoplasmic reticulum Ca2+ leak. Our findings indicate that FKBP12 deficiency during early development results in cardiac remodeling and altered expression of DCM-associated proteins that lead to progressive DCM in adult hearts, thus suggesting a major role for FKBP12 in embryonic cardiac muscle.

DOI: https://doi.org/10.1085/jgp.202413583
J Vis Exp. 2024 Nov 29.

Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model.

Yanjiani Xu, Jialiang Zhang, Jing Zhou, Yaoyu Zhang, Fangyang Huang, Mao Chen.

The underlying pathophysiological mechanisms of diabetic cardiomyopathy (DbCM), a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM), remain poorly understood. The myocardial toxicity associated with T2DM is attributed to factors such as lipotoxicity, glucotoxicity, oxidative stress, reduced cardiac efficiency, and lipoapoptosis. Compared to rats, mice offer greater accessibility, cost-effectiveness, and broader applicability for animal experiments. Insulin resistance and impaired insulin secretion are crucial factors in the pathophysiology of T2DM. We introduce a novel nongenetic murine model that replicates the progression of human DbCM induced by a combination of high-fat diet (HFD) feeding and streptozotocin (STZ) injection. In this study, we used wild-type C57BL/6J mice, administering an HFD regimen for 12 weeks, followed by intraperitoneal injections of STZ for an additional 12 weeks to induce characteristic manifestations of T2DM. We conducted oral glucose tolerance tests and measured serum insulin concentrations to confirm the development of insulin resistance and insufficient insulin secretion. Cardiac structure and function were rigorously assessed through noninvasive transthoracic echocardiography. Pathological characteristics were evaluated through Masson's trichrome staining and wheat germ agglutinin (WGA) staining, revealing pathological features related to DbCM. Therefore, we provide a robust and versatile method for establishing a nongenetic murine model of DbCM.

DOI: https://doi.org/10.3791/67189