bims-hafaim 2021-06-06 papers

bims-hafaim

Biomed News

on Heart Failure Metabolism

Issue of 2021‒06‒06
fourteen papers selected by
Kyle McCommis
Saint Louis University

KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy.
Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy.
AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure.
Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure.
PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.
Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice.
Salidroside protects cardiac function in mice with diabetic cardiomyopathy via activation of mitochondrial biogenesis and SIRT3.
Dapagliflozin in Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Rationale and Design of the DELIVER Trial.
Metabolic Effects of Empagliflozin in Heart Failure: A Randomized, Double-Blind, and Placebo-Controlled Trial (Empire HF Metabolic).
Insulin Signaling In the Heart.
Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts.
Ang II Promotes Cardiac Autophagy and Hypertrophy via Orai1/STIM1.
High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling.
Cardiomyocyte-specific Txnip C247S mutation improves left ventricular functional reserve in streptozotocin-induced diabetic mice.

BMC Cardiovasc Disord. 2021 May 31. 21(1): 266

KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy.

Yi Wang, Hongjuan Liao, Yueheng Wang, Jinlin Zhou, Feng Wang, Yingxin Xie, Kun Zhao, Weinian Gao.

  BACKGROUND: Cardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy.METHODS: Human and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR.
RESULTS: The mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy.
CONCLUSIONS: Our findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.

Keywords:  Akt; Cardiac hypertrophy; KLK11; MTOR; Protein synthesis

DOI:  https://doi.org/10.1186/s12872-021-02053-y
J Mol Cell Cardiol. 2021 May 31. pii: S0022-2828(21)00110-3. [Epub ahead of print]

Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy.

Giovannis E Davogustto, Rebecca L Salazar, Hernan G Vasquez, Anja Karlstaedt, William P Dillon, Patrick H Guthrie, Joseph R Martin, Heidi Vitrac, Gina De La Guardia, Deborah Vela, Aleix Ribas-Latre, Corrine Baumgartner, Kristin Eckel-Mahan, Heinrich Taegtmeyer.

  RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown.OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart.
METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased. While hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models.
CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.

Keywords:  Exercise; Glycolysis; Hypertrophy; Metabolism; mTORC1

DOI:  https://doi.org/10.1016/j.yjmcc.2021.05.016
Basic Res Cardiol. 2021 Jun 04. 116(1): 38

AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure.

Anca Remes, Andreas H Wagner, Nesrin Schmiedel, Markus Heckmann, Theresa Ruf, Lin Ding, Andreas Jungmann, Frauke Senger, Hugo A Katus, Nina D Ullrich, Norbert Frey, Markus Hecker, Oliver J Müller.

  Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

Keywords:  Adeno-associated virus; Cardiac hypertrophy; Decoy oligonucleotide; Heart failure; NFAT; Transcription factor

DOI:  https://doi.org/10.1007/s00395-021-00880-w
Circ Res. 2021 Jun 03.

Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure.

Jin-Ling Huo, Lemin Jiao, Qi An, Xiuying Chen, Yuruo Qi, Bingfei Wei, Yichao Zheng, Xiaojing Shi, Erhe Gao, Hong-Min Liu, Dong Chen, Cong Wang, Wen Zhao.

  Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. Methods and Results: Adult mouse cardiac fibroblasts (CFs)，neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.

Keywords:  LSD1; TGFβ; cardiac remodeling; knockout; myofibroblast

DOI:  https://doi.org/10.1161/CIRCRESAHA.120.318149
Cardiovasc Res. 2021 Jun 04. pii: cvab188. [Epub ahead of print]

PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.

Nikolay Naumenko, Maija Mutikainen, Lari Holappa, Jorge L Ruas, Tomi Tuomainen, Pasi Tavi.

  AIMS: Biological sex has fundamental effects on mammalian heart physiology and pathogenesis. While it has been established that female sex is a protective factor against most cardiovascular diseases (CVDs), this beneficial effect may involve pathways associated with cardiac energy metabolism. Our aim was to elucidate the role of transcriptional coactivator PGC-1α in sex dimorphism of heart failure development.METHODS AND RESULTS: Here we show that mice deficient in cardiac expression of the peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1α (PGC-1α) develop dilated heart failure associated with changes in aerobic and anaerobic metabolism, calcium handling, cell structure, electrophysiology as well as gene expression. These cardiac changes occur in both sexes, but female mice develop an earlier and more severe structural and functional phenotype associated with dyssynchronous local calcium release resulting from disruption of t-tubular structures of the cardiomyocytes.
CONCLUSIONS: These data reveal that the integrity of the subcellular Ca2+ release and uptake machinery is dependent on energy metabolism and that female hearts are more prone to suffer from contractile dysfunction in conditions with compromised production of cellular energy. Furthermore, these findings suggest that PGC-1α is a central mediator of sex-specific differences in heart function and CVD susceptibility.
TRANSLATIONAL PERSPECTIVE: Biological sex is an important variable in clinical medicine, cardiac physiology, and pathogenesis. However, sex-specific clinical practices or therapies are emerging slowly in the absence of deeper understanding of the specific mechanism behind sex dimorphism in cardiac disease progression. Here, we show that energy metabolism has a central role in sex dimorphism of heart failure progression and that a signalling cascade involving PGC-1α might have a role in it. We provide insights into sex specific mechanisms of heart failure development which are necessary to identify sex specific treatment practices for cardiovascular diseases.

Keywords:  Sex; energy metabolism; heart failure; local Ca2+ signalling; t-tubule

DOI:  https://doi.org/10.1093/cvr/cvab188
J Cell Mol Med. 2021 May 30.

Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice.

Shan Huang, Jiqun Wang, Hongbo Men, Yi Tan, Qian Lin, Evelyne Gozal, Yang Zheng, Lu Cai.

  To efficiently prevent diabetic cardiomyopathy (DCM), we have explored and confirmed that metallothionein (MT) prevents DCM by attenuating oxidative stress, and increasing expression of proteins associated with glucose metabolism. To determine whether Akt2 expression is critical to MT prevention of DCM, mice with either global Akt2 gene deletion (Akt2-KO), or cardiomyocyte-specific overexpressing MT gene (MT-TG) or both combined (MT-TG/Akt2-KO) were used. Akt2-KO mice exhibited symptoms of DCM (cardiac remodelling and dysfunction), and reduced expression of glycogen and glucose metabolism-related proteins, despite an increase in total Akt (t-Akt) phosphorylation. Cardiac MT overexpression in MT-TG/Akt2-KO mice prevented DCM and restored glucose metabolism-related proteins expression and baseline t-Akt phosphorylation. Furthermore, phosphorylation of ERK1/2 increased in the heart of MT-TG/Akt2-KO mice, compared with Akt2-KO mice. As ERK1/2 has been implicated in the regulation of glucose transport and metabolism this increase could potentially underlie MT protective effect in MT-TG/Akt2-KO mice. Therefore, these results show that although our previous work has shown that MT preserving Akt2 activity is sufficient to prevent DCM, in the absence of Akt2 MT may stimulate alternative or downstream pathways protecting from DCM in a type 2 model of diabetes, and that this protection may be associated with the ERK activation pathway.

Keywords:  Akt2 knock out; diabetes; glucose metabolism; insulin resistance; metallothionein

DOI:  https://doi.org/10.1111/jcmm.16687
Phytother Res. 2021 May 30.

Salidroside protects cardiac function in mice with diabetic cardiomyopathy via activation of mitochondrial biogenesis and SIRT3.

Ye Li, Xin Wei, Shu-Li Liu, Ying Zhao, Si Jin, Xiao-Yan Yang.

  To investigate the effects and the underlying mechanisms of salidroside on diabetic cardiomyopathy, diabetes was induced in mice by a long-term high-fat diet and a low-dose injection of streptozocin. Measurements of cardiac function, biochemical analysis, and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. In this study, we found that diabetic mice exhibited decreased cardiac systolic function and impaired mitochondrial ultrastructure. Pre-treatment with salidroside protected mice against myocardial dysfunction, reduced blood glucose, improved insulin resistance, and induced mitochondrial biogenesis. Neonatal rat cardiomyocytes were cultured to explore the mechanisms of salidroside in vitro. Salidroside alleviated decreased expression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM) via phosphorylation of 5' AMP-activated protein kinase (AMPK), which may be associated with mitochondrial biogenesis. Salidroside also increased sirtuin-3 (SIRT3) expression in cardiomyocytes. Furthermore, salidroside promoted the translocation of SIRT3 from cytoplasm to mitochondria and increased the deacetylation of mitochondrial proteins such as manganese-dependent superoxide dismutase (MnSOD). In Conclusion, salidroside not only improved diabetes, but also ameliorated diabetic cardiomyopathy, which was at least partly associated with the activation of mitochondrial SIRT3, AMPK/Akt, and PGC-1α/TFAM and subsequent improving mitochondrial function.

Keywords:  SIRT3; diabetic cardiomyopathy; mitochondrial biogenesis; salidroside

DOI:  https://doi.org/10.1002/ptr.7175
Eur J Heart Fail. 2021 May 29.

Dapagliflozin in Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Rationale and Design of the DELIVER Trial.

Scott D Solomon, Rudolf A de Boer, David DeMets, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Carolyn S P Lam, Felipe Martinez, Sanjiv J Shah, Daniel Lindholm, Ulrica Wilderäng, Fredrik Öhrn, Brian Claggett, Anna Maria Langkilde, Magnus Petersson, John J V McMurray.

BACKGROUND: Sodium glucose co-transporter type 2 (SGLT2) inhibitors, originally developed as glucose lowering agents, have been shown to reduce heart failure hospitalizations in patients with type 2 diabetes without established heart failure, and in patients with heart failure with and without diabetes. Their role in patients with heart failure with preserved and mildly reduced ejection fraction remains unknown.DESIGN AND METHODS: Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) is an international, multi-center, parallel group, event-driven, randomized, double-blind trial in patients with chronic heart failure and left ventricular ejection fraction (LVEF) greater than 40%, comparing the effect of dapagliflozin 10 mg, compared with placebo, once daily, in addition to standard of care. Patients with or without diabetes, with signs and symptoms of heart failure, a left ventricular ejection fraction > 40%, elevation in natriuretic peptides and evidence of structural heart disease are eligible. The primary endpoint is time to first cardiovascular death or worsening heart failure event (heart failure hospitalization or urgent heart failure visit), and will be assessed in dual primary analyses - the full population and in those with LVEF < 60%. The study is event drive and will target 1117 primary events. A total of 6263 patients have been randomized.
CONCLUSIONS: DELIVER will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with heart failure and preserved and mildly reduced ejection fraction. Clinicaltrials.gov NCT03619213. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ejhf.2249
Circulation. 2021 Jun;143(22): 2208-2210

Metabolic Effects of Empagliflozin in Heart Failure: A Randomized, Double-Blind, and Placebo-Controlled Trial (Empire HF Metabolic).

Jesper Jensen, Massar Omar, Caroline Kistorp, Christian Tuxen, Ida Gustafsson, Lars Køber, Finn Gustafsson, Jens Faber, Julie L Forman, Jacob E Møller, Morten Schou.



Keywords:  body composition; diabetes mellitus, type 2; empagliflozin; heart failure; insulin resistance; sodium-glucose transporter 2 inhibitors

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.053463
Am J Physiol Endocrinol Metab. 2021 May 31.

Insulin Signaling In the Heart.

E Dale Abel.

  Insulin receptors are highly expressed in the heart and vasculature. Insulin signaling regulates cardiac growth, survival, substrate uptake, utilization and mitochondrial metabolism. Insulin signaling modulates the cardiac responses to physiological and pathological stressors. Altered insulin signaling in the heart may contribute to the pathophysiology of ventricular remodeling and heart failure progression. Myocardial insulin signaling adapts rapidly to changes in the systemic metabolic milieu. What may initially represent an adaptation to protect the heart from carbo-toxicity, may contribute to amplifying the risk of heart failure in obesity and diabetes. This review article presents the multiple roles of insulin signaling in cardiac physiology and pathology and discusses the potential therapeutic consequences of modulating myocardial insulin signaling.

Keywords:  Heart; Insulin; Metabolism; Signal transduction

DOI:  https://doi.org/10.1152/ajpendo.00158.2021
Front Physiol. 2021 ;12 673145

Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts.

Weiwei Wu, Qingyun Qin, Yan Ding, Huimei Zang, Dong-Sheng Li, Mitzi Nagarkatti, Prakash Nagarkatti, Wenjuan Wang, Xuejun Wang, Taixing Cui.

  Burgeoning evidence has indicated that normal autophagy is required for nuclear factor erythroid 2-related factor (Nrf2)-mediated cardiac protection whereas autophagy inhibition turns on Nrf2-mediated myocardial damage and dysfunction in a setting of pressure overload (PO). However, such a concept remains to be fully established by a careful genetic interrogation in vivo. This study was designed to validate the hypothesis using a mouse model of PO-induced cardiomyopathy and heart failure, in which cardiac autophagy and/or Nrf2 activity are genetically inhibited. Myocardial autophagy inhibition was induced by cardiomyocyte-restricted (CR) knockout (KO) of autophagy related (Atg) 5 (CR-Atg5KO) in adult mice. CR-Atg5KO impaired cardiac adaptations while exacerbating cardiac maladaptive responses in the setting of PO. Notably, it also turned off Nrf2-mediated defense while switching on Nrf2-operated tissue damage in PO hearts. In addition, cardiac autophagy inhibition selectively inactivated extracellular signal regulated kinase (ERK), which coincided with increased nuclear accumulation of Nrf2 and decreased nuclear translocation of activated ERK in cardiomyocytes in PO hearts. Mechanistic investigation revealed that autophagy is required for the activation of ERK, which suppresses Nrf2-driven expression of angiotensinogen in cardiomyocytes. Taken together, these results provide direct evidence consolidating the notion that normal autophagy enables Nrf2-operated adaptation while switching off Nrf2-mediated maladaptive responses in PO hearts partly through suppressing Nrf2-driven angiotensinogen expression in cardiomyocytes.

Keywords:  ERK; Nrf2; autophagy; cardiac dysfunction; pressure overload

DOI:  https://doi.org/10.3389/fphys.2021.673145
Front Pharmacol. 2021 ;12 622774

Ang II Promotes Cardiac Autophagy and Hypertrophy via Orai1/STIM1.

Chang-Bo Zheng, Wen-Cong Gao, Mingxu Xie, Zhichao Li, Xin Ma, Wencong Song, Dan Luo, Yongxiang Huang, Jichen Yang, Peng Zhang, Yu Huang, Weimin Yang, Xiaoqiang Yao.

  The pathophysiology of cardiac hypertrophy is complex and multifactorial. Both the store-operated Ca2+ entry (SOCE) and excessive autophagy are the major causative factors for pathological cardiac hypertrophy. However, it is unclear whether these two causative factors are interdependent. In this study, we examined the functional role of SOCE and Orai1 in angiotensin II (Ang II)-induced autophagy and hypertrophy using in vitro neonatal rat cardiomyocytes (NRCMs) and in vivo mouse model, respectively. We show that YM-58483 or SKF-96365 mediated pharmacological inhibition of SOCE, or silencing of Orai1 with Orail-siRNA inhibited Ang II-induced cardiomyocyte autophagy both in vitro and in vivo. Also, the knockdown of Orai1 attenuated Ang II-induced pathological cardiac hypertrophy. Together, these data suggest that Ang II promotes excessive cardiomyocyte autophagy through SOCE/Orai1 which can be the prime contributing factors in cardiac hypertrophy.

Keywords:  Cardiac hypertrophy; SOCE; STIM1; angiotensin II; autophagy; orai1

DOI:  https://doi.org/10.3389/fphar.2021.622774
Front Physiol. 2021 ;12 648399

High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling.

Xietian Pan, Chengxiang Li, Haokao Gao.

  An increased vulnerability has been detected after ischemia/reperfusion injury in cardiomyocytes in diabetic patients. Glucagon-like peptide-1 (GLP-1) has been proven to have a notable cardioprotective effect in cardiomyocytes. However, in diabetic patients, the cardioprotective effects of GLP-1 are compromised, which is called GLP-1 resistance. β-arrestin is one of the two main downstream effectors of GLP-1 and β-arrestin signaling pathway exerts cardioprotective effects upon activation of GLP-1R. Our hypothesis is that the increased vulnerability of cardiomyocytes in diabetic patients is partly due to disruption of the β-arrestin signaling pathway. To test this, we analyzed cardiomyocyte viability and survival in high glucose and normal glucose condition after hypoxia/reoxygenation injury in vitro, additional GLP-1 was used to determine whether β-arrestin signaling pathway was involved. We also investigated the role of mitochondrial dysfunction in GLP-1 resistance. Our results showed that cardioprotective effects of GLP-1 were reduced in high glucose cultured H9C2 cells compared to normal glucose cultured H9C2, verifying the existence of GLP-1 resistance in high glucose cultured H9C2 cells. Further study suggested that β-arrestin plays a key role in GLP-1 resistance: β-arrestin expression is notably downregulated in high glucose condition and cardioprotective effects of GLP-1 can be diminished by downregulation of β-arrestin in normal glucose condition while upregulation of β-arrestin can restore cardioprotective effects of GLP-1 in high glucose condition. Then we explore how β-arrestin affects the cardioprotective effects of GLP-1 and found that β-arrestin exerts cardioprotective effects by improving mitochondria quality control via the PI3K/Akt signaling pathway. Thus, our study found out a new mechanism of GLP-1 resistance of cardiomyocytes in high glucose conditions that impaired β-arrestin expression, caused mitochondria dysfunction and eventually cell death. Our study provided a new perspective in treating myocardial ischemia/reperfusion injury in diabetic patients.

Keywords:  GLP-1; PI3K/Akt; diabetic cardiomyocyte; mitochondria dysfunction; β-arrestin

DOI:  https://doi.org/10.3389/fphys.2021.648399
Am J Physiol Heart Circ Physiol. 2021 Jun 04.

Cardiomyocyte-specific Txnip C247S mutation improves left ventricular functional reserve in streptozotocin-induced diabetic mice.

Nobuhiro Mukai, Yoshinobu Nakayama, Syed Amir Abdali, Jun Yoshioka.

  Underlying molecular mechanisms for the development of diabetic cardiomyopathy remain to be determined. Long-term exposure to hyperglycemia causes oxidative stress, which leads to cardiomyocyte dysfunction. Previous studies established the importance of thioredoxin-Interacting protein (Txnip) in cellular redox homeostasis and glucose metabolism. Txnip is a highly glucose-responsive molecule that interacts with the catalytic center of reduced thioredoxin and inhibits the antioxidant function of thioredoxin. Here, we show that the molecular interaction between Txnip and thioredoxin plays a pivotal role in the regulation of redox balance in the diabetic myocardium. High glucose increased Txnip expression, decreased thioredoxin activities, and caused oxidative stress in cells. The Txnip-thioredoxin complex was detected in cells with overexpressing wild-type Txnip but not Txnip cysteine 247 to serine (C247S) mutant that disrupts the intermolecular disulfide bridge. Then, diabetes was induced in cardiomyocyte-specific Txnip C247S knock-in mice and their littermate control animals by injections of streptozotocin (STZ). Prolonged hyperglycemia up-regulated myocardial Txnip expression in both genotypes. The absence of Txnip's inhibition of thioredoxin in Txnip C247S mutant hearts promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage by diabetes. Stress hemodynamic analysis uncovered that Txnip C247S knock-in hearts have a greater left ventricular contractile reserve than wild-type hearts under STZ-induced diabetic conditions. These results provide novel evidence that Txnip serves as a regulator of hyperglycemia-induced cardiomyocyte toxicities through direct inhibition of thioredoxin, and identify the single cysteine residue in Txnip as a therapeutic target for diabetic injuries.

Keywords:  Metabolism; Reactive Oxygen Species; Thioredoxin

DOI:  https://doi.org/10.1152/ajpheart.00174.2021