bims-hafaim 2023-02-12 papers

Issue of 2023–02–12
four papers selected by
Kyle McCommis, Saint Louis University

J Cardiovasc Aging. 2023 Jan;pii: 9. [Epub ahead of print]3(1):

The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure.

Benjamin Werbner, Omid Mohammad Tavakoli-Rouzbehani, Amir Nima Fatahian, Sihem Boudina.

This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions.

Keywords: Mitochondria; cardiac; fibroblasts; fibrosis; mitophagy; remodeling

DOI: https://doi.org/10.20517/jca.2022.42

bioRxiv. 2023 Jan 25. pii: 2023.01.25.525524. [Epub ahead of print]

SIRT2 inhibition protects against cardiac hypertrophy and heart failure.

Xiaoyan Yang, Hsiang-Chun Chang, Yuki Tatekoshi, Maryam Balibegloo, Rongxue Wu, Chunlei Chen, Tatsuya Sato, Jason Shapiro, Hossein Ardehali.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of heart failure (HF) and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 ( Sirt2 -/- ) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2 -/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitors reduces cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in the progression of HF and cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of this disorder.

DOI: https://doi.org/10.1101/2023.01.25.525524

J Lipid Atheroscler. 2023 Jan;12(1): 47-57

Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease.

Seyed Amirhossein Tabatabaei Dakhili, Amanda A Greenwell, John R Ussher.

Diabetic cardiomyopathy was originally described as the presence of ventricular dysfunction in the absence of coronary artery disease and/or hypertension. It is characterized by diastolic dysfunction and is more prevalent in people with diabetes than originally realized, leading to the suggestion in the field that it simply be referred to as diabetic heart disease. While there are currently no approved therapies for diabetic heart disease, a multitude of studies clearly demonstrate that it is characterized by several disturbances in myocardial energy metabolism. One of the most prominent changes in myocardial energy metabolism in diabetes is a robust impairment in glucose oxidation. Herein we will describe the mechanisms responsible for the diabetes-induced decline in myocardial glucose oxidation, and the pharmacological approaches that have been pursued to correct this metabolic disorder. With surmounting evidence that stimulating myocardial glucose oxidation can alleviate diastolic dysfunction and other pathologies associated with diabetic heart disease, this may also represent a novel strategy for decreasing the prevalence of heart failure with preserved ejection fraction in the diabetic population.

Keywords: Cardiac energetics; Diabetic cardiomyopathies; Diabetic heart disease; Diastolic dysfunction; Glucose oxidation; Pyruvate dehydrogenase

DOI: https://doi.org/10.12997/jla.2023.12.1.47

Res Sq. 2023 Jan 25. pii: rs.3.rs-2448086. [Epub ahead of print]

Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction.

Hossein Ardehali, Yuki Tatekoshi, Jason Shapiro, Mingyang Liu, George Bianco, Ayumi Tatekoshi, Adam De Jesus, Navid Koleini, J Andrew Wasserstrom, Wolfgang Dillmann, Samuel Weinberg.

Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but the underlying pathophysiology is not well-understood and treatment options are limited. Hexokinase-1 (HK1) mitochondrial-binding and protein O-GlcNAcylation are both altered in conditions with risk factors for HFpEF. Here we report a novel mouse model of HFpEF and show that HK1 mitochondrial-binding in endothelial cells (EC) is critical for the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 in ECs from HFpEF mice. Mice with deletion of the mitochondrial-binding-domain of HK1 spontaneously develop HFpEF, and their ECs display impaired angiogenic potential. Mitochondrial-bound HK1 associates with dolichyl-diphosphooligosaccharide-protein-glycosyltransferase (DDOST) and its mitochondrial dislocation decreases protein N-glycosylation. We also show that the spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine-transferase (OGT) increases protein O-GlcNAcylation by shifting the balance of the hexosamine-biosynthetic-pathway intermediate supply into the O-GlcNAcylation machinery. Pharmacological inhibition of OGT or EC-specific overexpression of O-GlcNAcase reverses angiogenic defects in ECs and the HFpEF phenotype, indicating that increased protein O-GlcNAcylation is responsible for the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation in ECs, and provides a potential new therapy for this disorder.

DOI: https://doi.org/10.21203/rs.3.rs-2448086/v1