bims-mimcad 2024-08-18 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–08–18
ten papers selected by
Henver Brunetta, Karolinska Institutet

The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice.
PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.
The Oxygen Cascade According to HFpEF Likelihood: A Focus on Sex Differences.
Anchored PKA synchronizes adrenergic phosphoregulation of cardiac Cav1.2 channels.
Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.
Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure.
Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial.
β3-Adrenergic receptor overexpression in cardiomyocytes preconditions mitochondria to withstand ischemia-reperfusion injury.
Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.

Mol Metab. 2024 Aug 11. pii: S2212-8778(24)00136-4. [Epub ahead of print] 102005

The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice.

Christopher E Shannon, Terry Bakewell, Marcel J Fourcaudot, Iriscilla Ayala, Annie A Smelter, Edgar A Hinostroza, Giovanna Romero, Mara Asmis, Leandro C Freitas Lima, Martina Wallace, Luke Norton.

   OBJECTIVE: The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.
METHODS: The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.
RESULTS: Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from Mpc1AD-/- mice were intrinsically incapable of incorporating pyruvate into triglycerides. In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in Mpc1AD-/- mice regardless of sex, even under conditions of zero dietary fat.
CONCLUSION: These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.

Keywords:  Adipose; glyceroneogenesis; lipogenesis; mitochondria; sexual dimorphism

DOI:  https://doi.org/10.1016/j.molmet.2024.102005
Diabetes. 2024 Aug 13. pii: db240240. [Epub ahead of print]

PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.

Xinyi Chen, Andrea Ruiz-Velasco, Zhiyong Zou, Susanne S Hille, Claire Ross, Oveena Fonseka, Sanskruti R Gare, Nasser Hawimel O Alatawi, Rida Raja, Jiayan Zhang, Namrita Kaur, Xiangjun Zhao, Henrietta Morrell-Davies, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Derk Frank, Martin K Rutter, Christian Pinali, Tao Wang, Tamer M A Mohamed, Oliver J Müller, Wei Liu.

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid-induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, due to increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid-induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy.

DOI: https://doi.org/10.2337/db24-0240
JACC Adv. 2024 Jul;3(7): 101039

The Oxygen Cascade According to HFpEF Likelihood: A Focus on Sex Differences.

Jan Verwerft, Stephen Foulkes, Youri Bekhuis, Sara Moura-Ferreira, Maarten Falter, Sarah Hoedemakers, Ruta Jasaityte, Jan Stassen, Lieven Herbots, Andre La Gerche, Mark J Haykowsky, Guido Claessen.

   Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF).
Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood.
Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student's t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression.
Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference -4.4 mL/kg/min [95% CI: -3.7 to -5.1 mL/kg/min]) secondary to a reduced O2 delivery (-0.5 L/min [95% CI: -0.4 to -0.6 L/min]) and less oxygen extraction (-2.9 mL/dL [95% CI: -2.5 to -3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (-1.2 g/dL [95% CI: -0.9 to -1.5 g/dL]) and smaller stroke volume (-15 mL [95% CI: -14 to -17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (-9 mL/m2 [95% CI: -8 to -11 mL/m2]) and mass (-12 g/m2 [95% CI: -9 to -14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001).
Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Keywords:  dyspnea; echocardiography; exercise testing; heart failure with preserved ejection fraction; oxygen transport and utilization; sex differences

DOI:  https://doi.org/10.1016/j.jacadv.2024.101039
J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02157-4. [Epub ahead of print] 107656

Anchored PKA synchronizes adrenergic phosphoregulation of cardiac Cav1.2 channels.

Lipeng Wang, Yi Chen, Jin Li, Ruth Westenbroek, Travis Philyaw, Ning Zheng, John D Scott, Qinghang Liu, William A Catterall.

  Adrenergic modulation of voltage gated Ca2+ currents is a context specific process. In the heart Cav1.2 channels initiate excitation-contraction coupling. This requires protein kinase A (PKA) phosphorylation of the small GTPase Rad (Ras associated with diabetes) and involves direct phosphorylation of a1 subunit of the Cav1.2 at Ser1700. A contributing factor is the proximity of PKA to the channel through association with A-kinase anchoring proteins (AKAPs). Disruption of PKA anchoring by the disruptor peptide AKAP-IS prevents up-regulation of Cav1.2 currents in tsA-201 cells. Biochemical analyses demonstrate that Rad does not function as an A-kinase anchoring protein. Electrophysiological recording shows that channel mutants lacking phosphorylation sites (Cav1.2 STAA) lose responsivity to the second messenger cAMP. Measurements in cardiomyocytes isolated from Rad-/- mice show that adrenergic activation of Cav1.2 is attenuated but not completely abolished. Whole animal electrocardiography studies reveal that cardiac selective Rad knockout mice exhibited higher baseline left-ventricular ejection fraction (EF), greater fractional shortening (FS), and increased heart rate as compared to control animals. Yet, each parameter of cardiac function was slightly elevated when Rad-/- mice were treated with the adrenergic agonist isoproterenol. Thus, phosphorylation of Cav1.2 and dissociation of phospho-Rad from the channel are local cAMP responsive events that act in concert to enhance L-type calcium currents. This convergence of local PKA regulatory events at the cardiac L-type calcium channel may permit maximal β-adrenergic influence on the fight-or-flight response.

Keywords:  AKAP; PKA; Rad; voltage-gated Ca(2+) channels; β-adrenergic stimulation

DOI:  https://doi.org/10.1016/j.jbc.2024.107656
Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2319724121

Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.

Jorge C Correia, Paulo R Jannig, Maya L Gosztyla, Igor Cervenka, Serge Ducommun, Stine M Præstholm, José M Dias, Kyle D Dumont, Zhengye Liu, Qishan Liang, Daniel Edsgärd, Olof Emanuelsson, Paul Gregorevic, Håkan Westerblad, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Johanna T Lanner, Ana I Teixeira, Gene W Yeo, Jorge L Ruas.

  Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Notably, although Zfp697 is expressed in several cell types in skeletal muscle, myofiber-specific Zfp697 genetic ablation in mice is sufficient to hinder the inflammatory and regenerative response to muscle injury, compromising functional recovery. We show that Zfp697 is an essential mediator of the interferon gamma response in muscle cells and that it functions primarily as an RNA-interacting protein, with a very high number of miRNA targets. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue remodeling and regeneration.

Keywords:  RNA-binding protein; Zfp697; inflammation; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2319724121
Circ Res. 2024 Aug 14.

Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure.

Jessica L Caldwell, Jessica D Clarke, Charlotte E R Smith, Christian Pinali, Callum J Quinn, Charles M Pearman, Aiste Adomaviciene, Emma J Radcliffe, Amy E Watkins, Margaux A Horn, Elizabeth F Bode, George W P Madders, Mark Eisner, David A Eisner, Andrew W Trafford, Katharine M Dibb.

   BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+.
METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patchclamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure.
RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and SERCA function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria.
CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.

Keywords:  heart failure; mitochondrial diseases; myocytes, cardiac; sarcoplasmic reticulum; volume electron microscopy

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324601
Nat Commun. 2024 Aug 12. 15(1): 6914

Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.

Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs, Peter Rehling.

Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.

DOI: https://doi.org/10.1038/s41467-024-51109-y
JAMA Cardiol. 2024 Aug 14.

Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial.

Dalane W Kitzman, Adriaan A Voors, Robert J Mentz, Gregory D Lewis, Shira Perl, Robin Myte, Grace Kaguthi, C David Sjöström, Christian Källgren, Sanjiv J Shah.

Importance: Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors' knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF.
Objective: To investigate the efficacy and safety of the novel urate transporter-1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level.
Design, Setting, and Participants: This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024.
Interventions: Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization.
Main Outcomes and Measures: Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events).
Results: Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro-brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, -59.6%; 95% CI, -64.4% to -54.2%) lowered SUA level to a greater extent than allopurinol (mean change, -37.6%; 95% CI, -45.3% to -28.9%) or placebo (mean change, 0.8%; 95% CI, -11.8% to 15.2%; P < .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, -0.56 to 1.10 mL/kg/min; allopurinol, -0.17 mL/kg/min; 95% CI, -1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, -0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, -3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group.
Conclusions and Relevance: Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF.
Trial Registration: ClinicalTrials.gov Identifier: NCT04327024.

DOI: https://doi.org/10.1001/jamacardio.2024.2435
Basic Res Cardiol. 2024 Aug 12.

β3-Adrenergic receptor overexpression in cardiomyocytes preconditions mitochondria to withstand ischemia-reperfusion injury.

Miguel Fernández-Tocino, Andrés Pun-Garcia, Mónica Gómez, Agustín Clemente-Moragón, Eduardo Oliver, Rocío Villena-Gutierrez, Sofía Trigo-Anca, Anabel Díaz-Guerra, David Sanz-Rosa, Belén Prados, Lara Del Campo, Vicente Andrés, Valentín Fuster, José Luis de la Pompa, Laura Cádiz, Borja Ibañez.

  β3-Adrenergic receptor (β3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since β3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human β3AR (hβ3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous β3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hβ3AR overexpression on top of endogenous β3AR expression. hβ3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific β3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hβ3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hβ3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte β3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.

Keywords:  Beta adrenergic receptor; Ischemia–reperfusion injury; Mitochondria; Mitophagy; Preconditioning

DOI:  https://doi.org/10.1007/s00395-024-01072-y
Circ Res. 2024 Aug 15.

Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.

Ling Tang, Huiliang Qiu, Bing Xu, Yajuan Su, Verah Nyarige, Pengsheng Li, Houjia Chen, Brady Killham, Jun Liao, Henderson Adam, Aaron Yang, Alexander Yu, Michelle Jang, Michael Rubart, Jingwei Xie, Wuqiang Zhu.

   BACKGROUND: Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI).
METHODS: A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot.
RESULTS: The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 and downstream profibrotic gene expression.
CONCLUSIONS: Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

Keywords:  animals; fibroblasts; heart failure; mice; myocardial infarction

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324608