bims-carmet 2022-01-09 papers

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

Front Cardiovasc Med. 2021 ;8 725532

Molecular Mechanisms and Epigenetic Regulation in Diabetic Cardiomyopathy.

Anupam Mittal, Rajni Garg, Ajay Bahl, Madhu Khullar.

Diabetes mellitus (DM) is an important lifestyle disease. Type 2 diabetes is one of the prime contributors to cardiovascular diseases (CVD) and diabetic cardiomyopathy (DbCM) and leads to increased morbidity and mortality in patients with DM. DbCM is a typical cardiac disease, characterized by cardiac remodeling in the presence of DM and in the absence of other comorbidities such as hypertension, valvular diseases, and coronary artery disease. DbCM is associated with defective cardiac metabolism, altered mitochondrial structure and function, and other physiological and pathophysiological signaling mechanisms such as oxidative stress, inflammation, myocardial apoptosis, and autophagy. Epigenetic modifiers are crucial players in the pathogenesis of DbCM. Thus, it is important to explore the role of epigenetic modifiers or modifications in regulating molecular pathways associated with DbCM. In this review, we have discussed the role of various epigenetic mechanisms such as histone modifications (acetylation and methylation), DNA methylation and non-coding RNAs in modulating molecular pathways involved in the pathophysiology of the DbCM.

Keywords: apoptosis; cardiac remodeling; diabetes mellitus; diabetic cardiomyopathy; epigenetics; mitochondrial function; oxidative stress

DOI: https://doi.org/10.3389/fcvm.2021.725532

J Cardiovasc Transl Res. 2022 Jan 04.

Lipid Droplet-a New Target in Ischemic Heart Disease.

Xiaoying Guo, Qi Shi, Wanqin Zhang, Zhongwen Qi, Hao Lv, Fujing Man, Yingyu Xie, Yaping Zhu, Junping Zhang.

Lipid droplet (LD) is a kind of subcellular organelle, which originates from the endoplasmic reticulum (ER). LDs can move flexibly between other organelles and store energy in the cells. In recent years, LDs and lipid droplet-associated proteins have attracted added attention at home and abroad, especially in cardiovascular diseases. Cardiovascular diseases, especially ischemic heart disease (IHD), have always been the focus of attention because of their high morbidity and mortality. Atherosclerosis and myocardial remodeling are two important pathologic processes of IHD, and LDs and other organelles are involved in the development of the disease. The interaction between LDs and ER is involved in the formation of foam cells in atherosclerosis. And LDs, mitochondria, and lysosomes also affect the remodeling of cardiomyocytes by affecting ROS production and regulating PI3K/AKT pathways. In this article, we will review the role of LDs in IHD.

Keywords: Atherosclerosis; Endoplasmic reticulum; Lipid droplets; Lysosome; Mitochondrial; Myocardial remodeling

DOI: https://doi.org/10.1007/s12265-021-10204-x

J Mol Cell Cardiol. 2021 Dec 31. pii: S0022-2828(21)00250-9. [Epub ahead of print]

Hypoxia signaling and oxygen metabolism in cardio-oncology.

Alan H Baik.

Cardio-oncology is a rapidly growing field in cardiology that focuses on the management of cardiovascular toxicities associated with cancer-directed therapies. Tumor hypoxia is a central driver of pathologic tumor growth, metastasis, and chemo-resistance. In addition, conditions that mimic hypoxia (pseudo-hypoxia) play a causal role in the pathogenesis of numerous types of cancer, including renal cell carcinoma. Therefore, therapies targeted at hypoxia signaling pathways have emerged over the past several years. Though efficacious, these therapies are associated with significant cardiovascular toxicities, ranging from hypertension to cardiomyopathy. This review focuses on oxygen metabolism in tumorigenesis, the role of targeting hypoxia signaling in cancer therapy, and the relevance of oxygen metabolism in cardio-oncology. This review will specifically focus on hypoxia signaling mediated by hypoxia-inducible factors and the prolyl hydroxylase oxygen-sensing enzymes, the cardiovascular effects of specific cancer targeted therapies mediated on VEGF and HIF signaling, hypoxic signaling in cardiovascular disease, and the role of oxygen in anthracycline cardiotoxicity. The implications of these therapies on myocardial biology and cardiac function are discussed, underlining the fine balance of hypoxia signaling in cardiac homeostasis. Understanding these cardiovascular toxicities will be important to optimize treatment for cancer patients while mitigating potentially severe cardiovascular side effects.

Keywords: Anthracycline; Cardio-oncology; Hypoxia signaling; Hypoxia-inducible factor; Oxygen metabolism; VEGF

DOI: https://doi.org/10.1016/j.yjmcc.2021.12.013