bims-hafaim 2022-01-09 papers

Issue of 2022–01–09
eight papers selected by
Kyle McCommis, Saint Louis University

Diabetologia. 2022 Jan 07.

Metabolic, structural and biochemical changes in diabetes and the development of heart failure.

Kim L Ho, Qutuba G Karwi, David Connolly, Simran Pherwani, Ezra B Ketema, John R Ussher, Gary D Lopaschuk.

Diabetes contributes to the development of heart failure through various metabolic, structural and biochemical changes. The presence of diabetes increases the risk for the development of cardiovascular disease (CVD), and since the introduction of cardiovascular outcome trials to test diabetic drugs, the importance of improving our understanding of the mechanisms by which diabetes increases the risk for heart failure has come under the spotlight. In addition to the coronary vasculature changes that predispose individuals with diabetes to coronary artery disease, diabetes can also lead to cardiac dysfunction independent of ischaemic heart disease. The hyperlipidaemic, hyperglycaemic and insulin resistant state of diabetes contributes to a perturbed energy metabolic milieu, whereby the heart increases its reliance on fatty acids and decreases glucose oxidative rates. In addition to changes in cardiac energy metabolism, extracellular matrix remodelling contributes to the development of cardiac fibrosis, and impairments in calcium handling result in cardiac contractile dysfunction. Lipotoxicity and glucotoxicity also contribute to impairments in vascular function, cardiac contractility, calcium signalling, oxidative stress, cardiac efficiency and lipoapoptosis. Lastly, changes in protein acetylation, protein methylation and DNA methylation contribute to a myriad of gene expression and protein activity changes. Altogether, these changes lead to decreased cardiac efficiency, increased vulnerability to an ischaemic insult and increased risk for the development of heart failure. This review explores the above mechanisms and the way in which they contribute to cardiac dysfunction in diabetes.

Keywords: Cardiac metabolism; Diabetes; Fatty acid oxidation; Fibrosis; Glucose oxidation; Glucotoxicity; Heart failure; Hypertrophy; Review

DOI: https://doi.org/10.1007/s00125-021-05637-7

Sci Rep. 2022 Jan 07. 12(1): 85

O-ring-induced transverse aortic constriction (OTAC) is a new simple method to develop cardiac hypertrophy and heart failure in mice.

Yasuhisa Nakao, Jun Aono, Mika Hamaguchi, Kayo Takahashi, Tomohisa Sakaue, Katsuji Inoue, Shuntaro Ikeda, Osamu Yamaguchi.

Suture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator's skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

DOI: https://doi.org/10.1038/s41598-021-04096-9

Front Immunol. 2021 ;12 790511

MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis.

Chao Zhong, Kisuk Min, Zhiqiang Zhao, Cheng Zhang, Erhe Gao, Yan Huang, Xinbo Zhang, Margaret Baldini, Rajika Roy, Xiaofeng Yang, Walter J Koch, Anton M Bennett, Jun Yu.

Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.

Keywords: MAPK signaling; MKP-5; cardiac fibrosis; extracellular matrix; macrophages

DOI: https://doi.org/10.3389/fimmu.2021.790511

Pflugers Arch. 2022 Jan;474(1): 33-61

Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy.

Carolina Jaquenod De Giusti, Julieta Palomeque, Alicia Mattiazzi.

Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart diseases such as valvular or coronary artery dysfunctions. Since the impact of DM on cardiac function is rather silent and slow, early stages of diabetic cardiomyopathy, known as prediabetes, are poorly recognized, and, on many occasions, cardiac illness is diagnosed only after a severe degree of dysfunction was reached. Therefore, exploration and recognition of the initial pathophysiological mechanisms that lead to cardiac dysfunction in diabetic cardiomyopathy are of vital importance for an on-time diagnosis and treatment of the malady. Among the complex and intricate mechanisms involved in diabetic cardiomyopathy, Ca2+ mishandling and mitochondrial dysfunction have been described as pivotal early processes. In the present review, we will focus on these two processes and the molecular pathway that relates these two alterations to the earlier stages and the development of diabetic cardiomyopathy.

Keywords: Calcium mishandling; Diabetic cardiomyopathy; Mitochondrial dysfunction

DOI: https://doi.org/10.1007/s00424-021-02650-y

J Clin Invest. 2022 Jan 06. pii: e152297. [Epub ahead of print]

TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis.

Haifeng Yin, Xiaoyun Guo, Yi Chen, Yachang Zeng, Xiaoliang Mo, Siqi Hong, Hui He, Jing Li, Rachel Steinmetz, Qinghang Liu.

Mutations in TAB2 (transforming growth factor β activated kinase 1 binding protein 2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing RIPK1 (receptor-interacting protein kinase 1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling following pathological stress. In cardiomyocytes, deletion of TAB2, but not its close homologue TAB3, promoted TNFα-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knock-in effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrate that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.

Keywords: Apoptosis; Cardiology; Cardiovascular disease; Cell Biology; Molecular biology

DOI: https://doi.org/10.1172/JCI152297

Animal Model Exp Med. 2021 Dec;4(4): 381-390

Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy.

Yahao Ling, Jiaxin Ma, Xiaolong Qi, Xu Zhang, Qi Kong, Feifei Guan, Wei Dong, Wei Chen, Shan Gao, Xiang Gao, Shuo Pan, Yuanwu Ma, Dan Lu, Lianfeng Zhang.

Background: Multiple mitochondrial dysfunction syndromes (MMDS) presents as complex mitochondrial damage, thus impairing a variety of metabolic pathways. Heart dysplasia has been reported in MMDS patients; however, the specific clinical symptoms and pathogenesis remain unclear. More urgently, there is a lack of an animal model to aid research. Therefore, we selected a reported MMDS causal gene, Isca1, and established an animal model of MMDS complicated with cardiac dysplasia.
Methods: The myocardium-specific Isca1 knockout heterozygote (Isca1 HET) rat was obtained by crossing the Isca1 conditional knockout (Isca1 cKO) rat with the α myosin heavy chain Cre (α-MHC-Cre) rat. Cardiac development characteristics were determined by ECG, blood pressure measurement, echocardiography and histopathological analysis. The responsiveness to pathological stimuli were observed through adriamycin treatment. Mitochondria and metabolism disorder were determined by activity analysis of mitochondrial respiratory chain complex and ATP production in myocardium.
Results: ISCA1 expression in myocardium exhibited a semizygous effect. Isca1 HET rats exhibited dilated cardiomyopathy characteristics, including thin-walled ventricles, larger chambers, cardiac dysfunction and myocardium fibrosis. Downregulated ISCA1 led to deteriorating cardiac pathological processes at the global and organizational levels. Meanwhile, HET rats exhibited typical MMDS characteristics, including damaged mitochondrial morphology and enzyme activity for mitochondrial respiratory chain complexes Ⅰ, Ⅱ and Ⅳ, and impaired ATP production.
Conclusion: We have established a rat model of MMDS complicated with cardiomyopathy, it can also be used as model of myocardial energy metabolism dysfunction and mitochondrial cardiomyopathy. This model can be applied to the study of the mechanism of energy metabolism in cardiovascular diseases, as well as research and development of drugs.

Keywords: ISCA1; cardiomyopathy; energy metabolism; multiple mitochondrial dysfunction syndromes (MMDS); rat model

DOI: https://doi.org/10.1002/ame2.12193

JAMA Netw Open. 2022 Jan 04. 5(1): e2142078

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Patients With Type 2 Diabetes and Other Risk Factors for Cardiovascular Disease: A Meta-analysis.

Mukul Bhattarai, Mohsin Salih, Manjari Regmi, Mohammad Al-Akchar, Radhika Deshpande, Zurain Niaz, Abhishek Kulkarni, Momin Siddique, Shruti Hegde.

Importance: The cardiovascular outcome in selected populations when sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are emerging as standard therapy is not clearly understood. It is important to learn the magnitude of cardiovascular benefit using SGLT2-Is across the select subgroups that include both sexes and multiple age and racial and ethnic groups.
Objectives: To evaluate the association between use of SGLT2-Is and cardiovascular benefits in a prespecified group in a larger sample size using data obtained from randomized clinical trials.
Data Sources: Search of electronic databases PubMed, Google Scholar, Web of Science, and Cochrane from inception to January 10, 2021, with additional studies identified through conference papers and meeting presentations, ClinicalTrials.gov, and reference lists of published studies.
Study Selection: Placebo-controlled randomized clinical trials in which participants had atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD, diabetes, or heart failure and which reported the primary outcome were included in this study. Multicenter observational and nonobservational studies and those with different outcomes of interest were excluded.
Data Extraction and Synthesis: Medical Subject Heading search terms included SGLT2-I and multiple cardiovascular outcomes in different combinations. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The analysis of all outcomes was performed using a Mantel-Haenszel equation and the random-effects model.
Main Outcomes and Measures: Six efficacy outcomes of SGLT2-I use (cardiovascular death and hospitalization for heart failure [HHF] as the primary outcome and major adverse cardiovascular event, HHF, cardiovascular death, acute myocardial infarction, and all-cause mortality as secondary outcomes), were evaluated. Subgroup analysis was performed for the primary outcome of cardiovascular death or HHF. Odds ratios (ORs) and 95% CIs were used to compare 2 interventions.
Results: Ten studies with 71 553 participants were included, among whom 39 053 received SGLT2-Is; among studies that reported these data, 28 809 were men and 15 655 were women (mean age, 65.2 [range, 61.9-70.0] years). Race and ethnicity were defined in the original trials and were categorized as Asian, Black, or other (6900 participants) and White (26 646 participants) for the purposes of this analysis (the category "other" was not specified consistently). In terms of age, 16 793 were younger than 65 years and 17 087 were 65 years or older. At a mean follow-up 2.3 (range, 0.8-4.2) years, the SGLT2-I group favored reduction in primary outcome (3165 of 39 053 [8.10%] vs 3756 of 32 500 [11.56%]; OR, 0.67 [95% CI, 0.55-0.80]; P < .001). No difference was noted in the rate of acute myocardial infarction compared with the placebo group (1256 of 26 931 [4.66%] vs 958 of 20 373 [4.70%]; OR, 0.95 [95% CI, 0.87-1.03]; P = .22). Subgroup analysis favored SGLT2-I use for the primary outcome in both sexes, age groups, and racial and ethnic groups.
Conclusions and Relevance: This meta-analysis supports that SGLT2-Is have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality in selected patients. Sodium-glucose cotransporter 2 inhibitors were not associated with reduced risk of acute myocardial infarction. Future long-term prospective studies are warranted to understand the long-term cardiovascular benefits.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.42078

Autophagy. 2022 Jan 05. 1-16

Restoration of mitophagy ameliorates cardiomyopathy in Barth syndrome.

Jun Zhang, Xueling Liu, Jia Nie, Yuguang Shi.

Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the TAFAZZIN/Taz gene which encodes a transacylase required for cardiolipin remodeling. Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining mitochondrial membrane structure, respiration, mtDNA biogenesis, and mitophagy. Mutations in the TAFAZZIN gene deplete mature cardiolipin, leading to mitochondrial dysfunction, dilated cardiomyopathy, and premature death in BTHS patients. Currently, there is no effective treatment for this debilitating condition. In this study, we showed that TAFAZZIN deficiency caused hyperactivation of MTORC1 signaling and defective mitophagy, leading to accumulation of autophagic vacuoles and dysfunctional mitochondria in the heart of Tafazzin knockdown mice, a rodent model of BTHS. Consequently, treatment of TAFAZZIN knockdown mice with rapamycin, a potent inhibitor of MTORC1, not only restored mitophagy, but also mitigated mitochondrial dysfunction and dilated cardiomyopathy. Taken together, these findings identify MTORC1 as a novel therapeutic target for BTHS, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for BTHS.Abbreviations: BTHS: Barth syndrome; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CL: cardiolipin; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; KD: knockdown; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LV: left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; OCR: oxygen consumption rate; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; qRT-PCR: quantitative real-time polymerase chain reaction; RPS6KB/S6K: ribosomal protein S6 kinase beta; SQSTM1/p62: sequestosome 1; TLCL: tetralinoleoyl cardiolipin; WT: wild-type.

Keywords: BTHS; MTORC1; TAFAZZIN; cardiolipin; mitophagy; rapamycin

DOI: https://doi.org/10.1080/15548627.2021.2020979