bims-hafaim 2022-10-16 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022‒10‒16
six papers selected by
Kyle McCommis
Saint Louis University

Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome.
Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure.
Alterations of Lipid Metabolism in the Heart in Spontaneously Hypertensive Rats Precedes Left Ventricular Hypertrophy and Cardiac Dysfunction.
Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity.
Dapagliflozin attenuates residual cardiac remodeling after surgical ventricular reconstruction in mice with an enlarged heart after myocardial infarction.
Cardiac Mitochondria Dysfunction in Dyslipidemic Mice.

Front Cardiovasc Med. 2022 ;9 997352

Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome.

Amanda A Greenwell, Seyed Amirhossein Tabatabaei Dakhili, Keshav Gopal, Christina T Saed, Jordan S F Chan, Nick Kazungu Mugabo, Pavel Zhabyeyev, Farah Eaton, Jennifer Kruger, Gavin Y Oudit, John R Ussher.

  Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.

Keywords:  Barth syndrome; cardiomyopathy; dichloroacetate; glucose oxidation; pyruvate dehydrogenase

DOI:  https://doi.org/10.3389/fcvm.2022.997352
Cell Metab. 2022 Oct 04. pii: S1550-4131(22)00398-9. [Epub ahead of print]

Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure.

Danielle Murashige, Jae Woo Jung, Michael D Neinast, Michael G Levin, Qingwei Chu, Jonathan P Lambert, Joanne F Garbincius, Boa Kim, Atsushi Hoshino, Ingrid Marti-Pamies, Kendra S McDaid, Swapnil V Shewale, Emily Flam, Steven Yang, Emilia Roberts, Li Li, Michael P Morley, Kenneth C Bedi, Matthew C Hyman, David S Frankel, Kenneth B Margulies, Richard K Assoian, John W Elrod, Cholsoon Jang, Joshua D Rabinowitz, Zoltan Arany.

  Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.

Keywords:  BCAA; Mendelian randomization; blood pressure; branched-chain amino acid; cardiac metabolism; cardiovascular metabolism; heart failure; hypertension; metabolomics

DOI:  https://doi.org/10.1016/j.cmet.2022.09.008
Cells. 2022 Sep 27. pii: 3032. [Epub ahead of print]11(19):

Alterations of Lipid Metabolism in the Heart in Spontaneously Hypertensive Rats Precedes Left Ventricular Hypertrophy and Cardiac Dysfunction.

Tomasz K Bednarski, Monika K Duda, Pawel Dobrzyn.

  Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes.

Keywords:  SHR rats; hypertension; hypertrophy; lipogenesis; lipolysis; myocardial metabolism; β-oxidation

DOI:  https://doi.org/10.3390/cells11193032
Front Pharmacol. 2022 ;13 930835

Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity.

Meng-Jiao Li, Wen-She Sun, Yang Yuan, Yu-Kun Zhang, Qi Lu, Yuan-Zhen Gao, Ting Ye, Dong-Ming Xing.

  Aims: The broad-spectrum anticancer drug doxorubicin (Dox) is associated with a high incidence of cardiotoxicity, which severely affects the clinical application of the drug and patients' quality of life. Here, we assess how Dox modulates myocardial energy and contractile function and this could aid the development of relevant protective drugs. Methods: Mice were subjected to doxorubicin and breviscapine treatment. Cardiac function was analyzed by echocardiography, and Dox-mediated signaling was assessed in isolated cardiomyocytes. The dual cardio-protective and anti-tumor actions of breviscapine were assessed in mouse breast tumor models. Results: We found that Dox disrupts myocardial energy metabolism by decreasing glucose uptake and increasing fatty acid oxidation, leading to a decrease in ATP production rate, an increase in oxygen consumption rate and oxidative stress, and further energy deficits to enhance myocardial fatty acid uptake and drive DIC development. Interestingly, breviscapine increases the efficiency of ATP production and restores myocardial energy homeostasis by modulating the serotonin-glucose-myocardial PI3K/AKT loop, increasing glucose utilization by the heart and reducing lipid oxidation. It enhances mitochondrial autophagy via the PINK1/Parkin pathway, eliminates damaged mitochondrial accumulation caused by Dox, reduces the degree of cardiac fibrosis and inflammation, and restores cardiac micro-environmental homeostasis. Importantly, its low inflammation levels reduce myeloid immunosuppressive cell infiltration, and this effect is synergistic with the anti-tumor effect of Dox. Conclusion: Our findings suggest that disruption of the cardiac metabolic network by Dox is an important driver of its cardiotoxicity and that serotonin is an important regulator of myocardial glucose and lipid metabolism. Myocardial energy homeostasis and timely clearance of damaged mitochondria synergistically contribute to the prevention of anthracycline-induced cardiotoxicity and improve the efficiency of tumor treatment.

Keywords:  DIC; PINK1/Parkin; breviscapine; doxorubicin; serotonin

DOI:  https://doi.org/10.3389/fphar.2022.930835
Biomed Pharmacother. 2022 Oct 10. pii: S0753-3322(22)01154-4. [Epub ahead of print]156 113765

Dapagliflozin attenuates residual cardiac remodeling after surgical ventricular reconstruction in mice with an enlarged heart after myocardial infarction.

Siyuan Ma, Lu Chen, Junyu Yan, Mengjia Shen, Rui Zhang, Mingjue Li, Mingyuan He, Kaitong Chen, Yingqi Zhu, Hairuo Lin, Yuegang Wang, Wangjun Liao, Jianping Bin, Cankun Zheng, Yulin Liao.

  BACKGROUND: Severe heart failure refractory to conventional therapy requires alternative treatment modalities. Surgical ventricular reconstruction (SVR) has been used to reverse cardiac remodeling in post-myocardial infarction (MI) patients with large left ventricular (LV) aneurysm, however, residual LV remodeling and dysfunction remain postoperatively. It is unclear whether SVR recovers response to drug treatment and whether the sodium-glucose co-transporter 2 inhibitor dapagliflozin (DAPA) reverses residual LV remodeling after SVR.METHODS: Adult male C57 mice were subjected to MI or sham surgery. Four-week later, MI mice with LV aneurysm underwent modified SVR or second open-chest sham operation and were randomized to DAPA or vehicle for four-week. Cardiac remodeling, LV function, and the underlying mechanisms were evaluated by echocardiography, invasive LV hemodynamic measurements, mRNA sequencing, and bioinformatics analysis.
RESULTS: SVR significantly decreased LV volume; increased myocardial strain, LV pressure change rates and end-systolic elastance; and decreased heart-to-body weight ratio and myocardial fibrosis. However, significant residual cardiac remodeling remained. DAPA significantly attenuated residual cardiac remodeling and improved LV function in SVR mice but did not have curative effects in non-SVR mice. Of the 1532 genes differentially expressed in SVR and MI mice, 1037 were associated with cardiac metabolism; Src, Crebbp, Fn1, Grb2, and Mapk14 were the top 5 hub genes. Unlike sham surgery, MI upregulated those 5 genes, and treatment with SVR + DAPA normalized their expression.
CONCLUSIONS: SVR restores therapeutic response in the post-MI heart with large LV aneurysm, and DAPA attenuates residual cardiac remodeling after SVR by normalizing some cardiac metabolism-related hub genes.

Keywords:  Cardiac metabolism; Dapagliflozin; Myocardial infarction; Residual cardiac remodeling; Surgical ventricular reconstruction

DOI:  https://doi.org/10.1016/j.biopha.2022.113765
Int J Mol Sci. 2022 Sep 29. pii: 11488. [Epub ahead of print]23(19):

Cardiac Mitochondria Dysfunction in Dyslipidemic Mice.

Alicja Braczko, Barbara Kutryb-Zajac, Agata Jedrzejewska, Oliwia Krol, Paulina Mierzejewska, Magdalena Zabielska-Kaczorowska, Ewa M Slominska, Ryszard T Smolenski.

  Dyslipidemia triggers many severe pathologies, including atherosclerosis and chronic inflammation. Several lines of evidence, including our studies, have suggested direct effects of dyslipidemia on cardiac energy metabolism, but details of these effects are not clear. This study aimed to investigate how mild dyslipidemia affects cardiac mitochondria function and vascular nucleotide metabolism. The analyses were performed in 3- and 6-month-old knock-out mice for low-density lipoprotein receptor (Ldlr-/-) and compared to wild-type C57Bl/6J mice (WT). Cardiac isolated mitochondria function was analyzed using Seahorse metabolic flux analyzer. The mechanical function of the heart was measured using echocardiography. The levels of fusion, fission, and mitochondrial biogenesis proteins were determined by ELISA kits, while the cardiac intracellular nucleotide concentration and vascular pattern of nucleotide metabolism ecto-enzymes were analyzed using reverse-phase high-performance liquid chromatography. We revealed the downregulation of mitochondrial complex I, together with a decreased activity of citrate synthase (CS), reduced levels of nuclear respiratory factor 1 and mitochondrial fission 1 protein, as well as lower intracellular adenosine and guanosine triphosphates' pool in the hearts of 6-month Ldlr-/- mice vs. age-matched WT. The analysis of vascular ecto-enzyme pattern revealed decreased rate of extracellular adenosine monophosphate hydrolysis and increased ecto-adenosine deaminase activity (eADA) in 6-month Ldlr-/- vs. WT mice. No changes were observed in echocardiography parameters in both age groups of Ldlr-/- mice. Younger hyperlipidemic mice revealed no differences in cardiac mitochondria function, CS activity, intracellular nucleotides, mitochondrial biogenesis, and dynamics but exhibited minor changes in vascular eADA activity vs. WT. This study revealed that dysfunction of cardiac mitochondria develops during prolonged mild hyperlipidemia at the time point corresponding to the formation of early vascular alterations.

Keywords:  LDL; heart; hyperlipidemia; mice; mitochondria; nucleotides

DOI:  https://doi.org/10.3390/ijms231911488