bims-hafaim 2022-03-13 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–03–13
nine papers selected by
Kyle McCommis, Saint Louis University

Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling.
Mitochondria in Pathological Cardiac Remodeling.
Cardiac specific knock-down of peroxisome proliferator activated receptor α prevents fasting-induced cardiac lipid accumulation and reduces perilipin 2.
Evaluation of Parkin in the Regulation of Myocardial Mitochondria-Associated Membranes and Cardiomyopathy During Endotoxemia.
Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control.
Abnormal mitochondrial function and morphology in heart transplanted patients with cardiac allograft vasculopathy.
Citri Reticulatae Pericarpium alleviates postmyocardial infarction heart failure by upregulating PPARγ expression.
Docosahexaenoic Acid-Enhanced Autophagic Flux Improves Cardiac Dysfunction after Myocardial Infarction by Targeting the AMPK/mTOR Signaling Pathway.
Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.

Am J Physiol Heart Circ Physiol. 2022 Mar 11.

Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling.

Sachiko Yoshikawa, Manabu Nagao, Ryuji Toh, Masakazu Shinohara, Takuya Iino, Yasuhiro Irino, Makoto Nishimori, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Tatsuro Ishida, Ken-Ichi Hirata.

  Alterations in cardiac metabolism are strongly associated with the pathogenesis of heart failure (HF). We recently reported that glutamine-dependent anaplerosis, termed glutaminolysis, was activated by H2O2 stimulation in rat cardiomyocytes, which seemed to be an adaptive response by which cardiomyocytes survive acute stress. However, the molecular mechanisms and fundamental roles of glutaminolysis in the pathophysiology of the failing heart are still unknown. Here, we treated wild-type mice (C57BL/6J) and rat neonatal cardiomyocytes (RNCMs) and fibroblasts (RNCFs) with angiotensin II (Ang II) to induce pathological cardiac remodeling. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was significantly increased in Ang II-induced mouse hearts, RNCMs and RNCFs. Unexpectedly, a GLS1 inhibitor attenuated Ang II-induced left ventricular hypertrophy and fibrosis in the mice, and gene knockdown and pharmacological perturbation of GLS1 suppressed hypertrophy and the proliferation of RNCMs and RNCFs, respectively. Using mass spectrometry (MS)-based stable isotope tracing with 13C-labeled glutamine, we observed glutamine metabolic flux in Ang II-treated RNCMs and RNCFs. The incorporation of 13C atoms into tricarboxylic acid (TCA) cycle intermediates and their derivatives was markedly enhanced in both cell types, indicating the activation of glutaminolysis in hypertrophied heart. Notably, GLS1 inhibition reduced the production of glutamine-derived aspartate and citrate, which are required for the biosynthesis of nucleic acids and lipids, possibly contributing to the suppression of cardiac hypertrophy and fibrosis. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibition of this anaplerotic pathway could be a novel therapeutic approach for HF.

Keywords:  glumaminase1; glutamine; glutaminolysis; heart failure; metabolic remodeling

DOI:  https://doi.org/10.1152/ajpheart.00692.2021
Curr Opin Physiol. 2022 Feb;pii: 100489. [Epub ahead of print]25

Mitochondria in Pathological Cardiac Remodeling.

Michael P Lazaropoulos, John W Elrod.

  Adverse cardiac remodeling is often precipitated by chronic stress or injury inflicted upon the heart during the progression of cardiovascular diseases. Mitochondria play an important role in the cardiomyocyte response to stress by serving as a signaling hub for changes in cellular energetics, redox balance, contractile function, and cell death. Cardiac remodeling involves alterations to mitochondrial form and function that are either compensatory to maintain contractility or maladaptive, which promotes heart failure progression. In this mini-review, we focus on three mitochondrial processes that contribution to cardiac remodeling: Ca2+ signaling, mitochondrial dynamics, and mitochondrial metabolism.

Keywords:  calcium; heart failure; metabolism; mitochondria; remodeling

DOI:  https://doi.org/10.1016/j.cophys.2022.100489
PLoS One. 2022 ;17(3): e0265007

Cardiac specific knock-down of peroxisome proliferator activated receptor α prevents fasting-induced cardiac lipid accumulation and reduces perilipin 2.

Natasha Fillmore, Vincent Hou, Junhui Sun, Danielle Springer, Elizabeth Murphy.

While fatty acid metabolism is altered under physiological conditions, alterations can also be maladaptive in diseases such as diabetes and heart failure. Peroxisome Proliferator Activated Receptor α (PPARα) is a transcription factor that regulates fat metabolism but its role in regulating lipid storage in the heart is unclear. The aim of this study is to improve our understanding of how cardiac PPARα regulates cardiac health and lipid accumulation. To study the role of cardiac PPARα, tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR-/-) were treated for 5 days with tamoxifen and then studied after 1-2 months. Under baseline conditions, cPPAR-/- mice appear healthy with normal body weight and mortality is not altered. Importantly, cardiac hypertrophy or reduced cardiac function was also not observed at baseline. Mice were fasted to elevate circulating fatty acids and induce cardiac lipid accumulation. After fasting, cPPAR-/- mice had dramatically lower cardiac triglyceride levels than control mice. Interestingly, cPPAR-/- hearts also had reduced Plin2, a key protein involved in lipid accumulation and lipid droplet regulation, which may contribute to the reduction in cardiac lipid accumulation. Overall, this suggests that a decline in cardiac PPARα may blunt cardiac lipid accumulation by decreasing Plin2 and that independent of differences in systemic metabolism a decline in cardiac PPARα does not seem to drive pathological changes in the heart.

DOI: https://doi.org/10.1371/journal.pone.0265007
Front Cell Dev Biol. 2022 ;10 796061

Evaluation of Parkin in the Regulation of Myocardial Mitochondria-Associated Membranes and Cardiomyopathy During Endotoxemia.

Matthew Kim, Azadeh Nikouee, Yuxiao Sun, Qing-Jun Zhang, Zhi-Ping Liu, Qun Sophia Zang.

  Background: Mitochondrial deficiency is a known pathology in sepsis-induced organ failure. We previously found that mitochondria-associated membranes (MAMs), a subcellular domain supporting mitochondrial status, are impaired in the heart during endotoxemia, suggesting a mechanism of mitochondrial damage occurred in sepsis. Mitophagy pathway via E3 ubiquitin ligase Parkin and PTEN-induced kinase 1 (PINK1) controls mitochondrial quality. Studies described here examined the impact of Parkin on cardiac MAMs and endotoxemia-induced cardiomyopathy. Additionally, point mutation W403A in Parkin was previously identified as a constitutively active mutation in vitro. In vivo effects of forced expression of this mutation were evaluated in the endotoxemia model. Methods: Mice of wild type (WT), Parkin-deficiency (Park2 -/- ), and knock-in expression of Parkin W402A (human Parkin W403A) were given lipopolysaccharide (LPS) challenge. Cardiac function was evaluated by echocardiography. In the harvested heart tissue, MAM fractions were isolated by ultracentrifugation, and their amount and function were quantified. Ultrastructure of MAMs and mitochondria was examined by electron microscopy. Mitochondrial respiratory activities were measured by enzyme assays. Myocardial inflammation was estimated by levels of pro-inflammatory cytokine IL-6. Myocardial mitophagy was assessed by levels of mitophagy factors associated with mitochondria and degrees of mitochondria-lysosome co-localization. Parkin activation, signified by phosphorylation on serine 65 of Parkin, was also evaluated. Results: Compared with WT, Park2 -/- mice showed more severely impaired cardiac MAMs during endotoxemia, characterized by disrupted structure, reduced quantity, and weakened transporting function. Endotoxemia-induced cardiomyopathy was intensified in Park2 -/- mice, shown by worsened cardiac contractility and higher production of IL-6. Mitochondria from the Park2 -/- hearts were more deteriorated, indicated by losses in both structural integrity and respiration function. Unexpectedly, mice carrying Parkin W402A showed similar levels of cardiomyopathy and mitochondrial damage when compared with their WT counterparts. Further, Parkin W402A mutation neither enhanced mitophagy nor increased Parkin activation in myocardium under the challenge of endotoxemia. Conclusion: our results suggest that Parkin/PINK1 mitophagy participates in the regulation of cardiac MAMs during endotoxemia. Point mutation W402A (human W403A) in Parkin is not sufficient to alleviate cardiomyopathy induced by endotoxemia in vivo.

Keywords:  cardiac dysfunction; endotoxemia; inflammation; mitochondria; mitophagy; parkin; sepsis

DOI:  https://doi.org/10.3389/fcell.2022.796061
Redox Biol. 2022 Feb 28. pii: S2213-2317(22)00047-7. [Epub ahead of print]51 102275

Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control.

Seong Keun Sonn, Eun Ju Song, Seungwoon Seo, Young Yeon Kim, Jee-Hyun Um, Franklin Joonyeop Yeo, Da Seul Lee, Sejin Jeon, Mi-Ni Lee, Jing Jin, Hyae Yon Kweon, Tae Kyeong Kim, Sinai Kim, Shin Hye Moon, Sue Goo Rhee, Jongkyeong Chung, Jaemoon Yang, Jin Han, Eui-Young Choi, Sung Bae Lee, Jeanho Yun, Goo Taeg Oh.

  Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure.

Keywords:  Damaged mitochondria; Heart failure; Mitochondrial quality control; Mitophagy; PINK1; Peroxiredoxin 3

DOI:  https://doi.org/10.1016/j.redox.2022.102275
J Heart Lung Transplant. 2022 Feb 03. pii: S1053-2498(22)01395-X. [Epub ahead of print]

Abnormal mitochondrial function and morphology in heart transplanted patients with cardiac allograft vasculopathy.

Emil Dariush Lichscheidt, Nichlas Riise Jespersen, Bent Roni Ranghøj Nielsen, Katrine Berg, Jacob Seefeldt, Jens Randel Nyengaard, Hans Erik Bøtker, Hans Eiskjær.

   BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival of HTx patients. Mitochondrial dysfunction has been reported in both arteriosclerotic coronary disease and heart failure. However, myocardial mitochondrial function has not been examined in HTx patients with CAV.
METHODS: 43 HTx patients (21 patients with CAV and 22 patients without CAV) ≥12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Number and area of mitochondria profiles as well as cristae morphology were assessed by transmission electron microscopy. Echocardiography and coronary angiography were used to measure global longitudinal strain (GLS) and grade CAV.
RESULTS: Complex I+II-linked respiration was reduced in patients with CAV compared with patients without CAV (82.7 ± 31.9 pmol O2/(s•mg) vs 116 ± 35.9 pmol O2/(s•mg), p = 0.003). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with left ventricular GLS (r = 0.49, p = 0.002) and negatively associated with elevated biomarkers (Troponin T: r=-0.33, p = 0.04 and NT-proBNP: r = -0.41, p = 0.009). Mitochondrial profile number and area did not differ. However, patients with CAV had a larger proportion of mitochondria with abnormal cristae morphology (p < 0.001).
CONCLUSIONS: Myocardial mitochondrial respiration is impaired in patients with CAV and is associated with an abnormal cristae morphology. The mitochondrial dysfunction appears to be associated with reduced myocardial contractile function and elevated biomarkers. These results highlight that mitochondrial targeted treatment in patients with CAV should be assessed in future clinical studies.

Keywords:  basic; cardiac allograft vasculopathy; heart failure; metabolism; mitochondria; translational and Clinical Research; vascular disease

DOI:  https://doi.org/10.1016/j.healun.2022.01.1376
Clin Exp Pharmacol Physiol. 2022 Mar 12.

Citri Reticulatae Pericarpium alleviates postmyocardial infarction heart failure by upregulating PPARγ expression.

Mengli Chen, Hongyan Zhu, Qingqing Zhu, Xiaodong Wu, Yufei Zhou, Rongrong Gao, Mengsha Shi, Ting Zhang, Ting Yin, Haifeng Zhang, Hongcai Shang, Xinli Li.

  Heart failure after myocardial infarction (MI) is the leading cause of death worldwide. Citri Reticulatae Pericarpium (CRP) is a traditional Chinese herbal medicine that has been used in the clinic for centuries. In this study, we aimed to investigate the roles of CRP in cardiac remodeling and heart failure after MI, as well as the molecular mechanisms involved. Male C57BL/6 mice aged 8 weeks were subjected to coronary artery ligation to mimic the clinical situation in vivo. Echocardiography was used to assess the systolic function of the mouse heart. Masson trichrome staining and Wheat germ agglutinin (WGA) staining were utilized to determine the fibrotic area and cross-sectional area of the mouse heart, respectively. Cardiomyocytes and fibroblasts were isolated from neonatal rats aged 0-3 days in vitro using enzyme digestion. TUNEL staining and EdU staining were performed to evaluate apoptosis and proliferation, respectively. Gene expression changes were analyzed by qRT-PCR, and protein expression changes were assessed by Western blotting. Our findings revealed that CRP attenuated cardiac hypertrophy, fibrosis and apoptosis and alleviated heart failure after MI in vivo. Furthermore, CRP mitigated cardiomyocyte apoptosis and fibroblast proliferation and differentiation into myofibroblasts. In addition, the PPARγ inhibitor T0070907 completely abolished the abovementioned beneficial effects of CRP, and the PPARγ activator rosiglitazone failed to further ameliorate cardiac apoptosis and fibrosis in vitro. CRP alleviates cardiac hypertrophy, fibrosis, and apoptosis and can ameliorate heart failure after MI via activation of PPARγ. This article is protected by copyright. All rights reserved.

Keywords:  Citri Reticulatae Pericarpium; Heart failure; Myocardial infarction; PPARγ

DOI:  https://doi.org/10.1111/1440-1681.13642
Oxid Med Cell Longev. 2022 ;2022 1509421

Docosahexaenoic Acid-Enhanced Autophagic Flux Improves Cardiac Dysfunction after Myocardial Infarction by Targeting the AMPK/mTOR Signaling Pathway.

Youyang Shi, Hao Li, Tingting Wu, Qiaoyu Wang, Qiongjun Zhu, Xueqiang Guan, Rongzhou Wu.

Background and Purpose. Docosahexaenoic acid (DHA) is a type of polyunsaturated fatty acid enriched in cod liver oil and seaweed. It is necessary for the human body and has important functions, such as antioxidation and antiatherosclerosis activities. Long-term oral administration of DHA or the use of DHA at the initial stage of ischemia can increase the level of autophagy and exert a protective effect on neurological functions related to cerebral infarction. However, the effect of DHA on myocardial injury and cardiac insufficiency after myocardial infarction (MI) is unknown. This study was aimed at exploring whether DHA plays a protective role in AMI and its specific molecular mechanism. Experimental Method. In vitro cardiomyocyte hypoxia and in vivo MI injury models were used to determine the role of DHA in MI. Hypoxic injury induced damage in cultured neonatal mouse cardiomyocytes (NMCs). The C57BL/6J mouse MI model was established by permanent ligation of the left anterior descending branch. Main Results. DHA improved the cardiomyocyte viability of NMCs induced by hypoxia injury and reduced cell necrosis. DHA reduced infarct size, improved heart function, and reduced the degree of myocardial fibrosis in mice after MI. In addition, DHA enhanced autophagy flux and reduced apoptosis in vitro and in vivo. In addition, we found that chloroquine, an autophagy inhibitor, blocked the protective effect of DHA on cardiomyocyte apoptosis and cardiac dysfunction, indicating that DHA exerts cardioprotective effects in part by promoting autophagy flux. We also observed that DHA enhanced autophagy flux by activating the AMPK/mTOR signaling pathway. Conclusions and Significance. In conclusion, our findings indicate for the first time that DHA improves MI-induced cardiac dysfunction by promoting AMPK/mTOR-mediated autophagic flux.

DOI: https://doi.org/10.1155/2022/1509421
Cell Rep. 2022 Mar 08. pii: S2211-1247(22)00208-X. [Epub ahead of print]38(10): 110475

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.

Nicole M Sayles, Nneka Southwell, Kevin McAvoy, Kihwan Kim, Alba Pesini, Corey J Anderson, Catarina Quinzii, Suzanne Cloonan, Hibiki Kawamata, Giovanni Manfredi.

  Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.

Keywords:  1C metabolism; CHCHD10; coiled-coil-helix-coiled-coil-helix domain containing 10; heart, cardiomyopathy; heme; integrated stress response; metabolic rewiring; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2022.110475