bims-hafaim 2023-09-17 papers

Issue of 2023‒09‒17
five papers selected by
Kyle McCommis, Saint Louis University

Basic Res Cardiol. 2023 Sep 09. 118(1): 37

Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.

Casper Homilius, Jacob Marthinsen Seefeldt, Julie Sørensen Axelsen, Tina Myhre Pedersen, Trine Monberg Sørensen, Roni Nielsen, Henrik Wiggers, Jakob Hansen, Vladimir V Matchkov, Hans Erik Bøtker, Ebbe Boedtkjer.

The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output and myocardial perfusion without affecting blood pressure in humans, but the cardiovascular sites of action remain obscure. Here, we test the hypothesis in rats that 3-OHB acts directly on the heart to increase cardiac contractility and directly on blood vessels to lower systemic vascular resistance. We investigate effects of 3-OHB on (a) in vivo hemodynamics using echocardiography and invasive blood pressure measurements, (b) isolated perfused hearts in Langendorff systems, and (c) isolated arteries and veins in isometric myographs. We compare Na-3-OHB to equimolar NaCl added to physiological buffers or injection solutions. At plasma concentrations of 2-4 mM in vivo, 3-OHB increases cardiac output (by 28.3±7.8%), stroke volume (by 22.4±6.0%), left ventricular ejection fraction (by 13.3±4.6%), and arterial dP/dtmax (by 31.9±11.2%) and lowers systemic vascular resistance (by 30.6±11.2%) without substantially affecting heart rate or blood pressure. Applied to isolated perfused hearts at 3-10 mM, 3-OHB increases left ventricular developed pressure by up to 26.3±7.4 mmHg and coronary perfusion by up to 20.2±9.5%. Beginning at 1-3 mM, 3-OHB relaxes isolated coronary (EC50=12.4 mM), cerebral, femoral, mesenteric, and renal arteries as well as brachial, femoral, and mesenteric veins by up to 60% of pre-contraction within the pathophysiological concentration range. Of the two enantiomers that constitute racemic 3-OHB, D-3-OHB dominates endogenously; but tested separately, the enantiomers induce similar vasorelaxation. We conclude that increased cardiac contractility and generalized systemic vasorelaxation can explain the elevated cardiac output during 3-OHB administration. These actions strengthen the therapeutic rationale for 3-OHB in heart failure management.

Keywords: 3-hydroxybutyrate; Contractile function; Enantiomers; Ketone bodies; Metabolism; Vasorelaxation

DOI: https://doi.org/10.1007/s00395-023-01008-y

Dis Model Mech. 2023 Sep 11. pii: dmm.050114. [Epub ahead of print]

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.

Nicole M Sayles, Jill S Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi.

Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion, YG8-800, KIKO-700, and FxnG127V. Few metabolites were changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Keywords: Cardiomyopathy; Frataxin; Friedreich Ataxia; Integrated stress response; Mitochondria; Mouse model

DOI: https://doi.org/10.1242/dmm.050114

Sci Rep. 2023 Sep 12. 13(1): 15022

Left ventricular hypertrophy and metabolic resetting in the Notch3-deficient adult mouse heart.

Francesca Del Gaudio, Dongli Liu, Maarja Andaloussi Mäe, Eike-Benjamin Braune, Emil M Hansson, Qing-Dong Wang, Christer Betsholtz, Urban Lendahl.

The heart depends on a functional vasculature for oxygenation and transport of nutrients, and it is of interest to learn how primary impairment of the vasculature can indirectly affect cardiac function and heart morphology. Notch3-deficiency causes vascular smooth muscle cell (VSMC) loss in the vasculature but the consequences for the heart remain largely elusive. Here, we demonstrate that Notch3-/- mice have enlarged hearts with left ventricular hypertrophy and mild fibrosis. Cardiomyocytes were hypertrophic but not hyperproliferative, and the expression of several cardiomyocyte markers, including Tnt2, Myh6, Myh7 and Actn2, was altered. Furthermore, expression of genes regulating the metabolic status of the heart was affected: both Pdk4 and Cd36 were downregulated, indicating a metabolic switch from fatty acid oxidation to glucose consumption. Notch3-/- mice furthermore showed lower liver lipid content. Notch3 was expressed in heart VSMC and pericytes but not in cardiomyocytes, suggesting that a perturbation of Notch signalling in VSMC and pericytes indirectly impairs the cardiomyocytes. In keeping with this, Pdgfbret/ret mice, characterized by reduced numbers of VSMC and pericytes, showed left ventricular and cardiomyocyte hypertrophy. In conclusion, we demonstrate that reduced Notch3 or PDGFB signalling in vascular mural cells leads to cardiomyocyte dysfunction.

DOI: https://doi.org/10.1038/s41598-023-42010-7

Curr Drug Targets. 2023 Sep 07.

Sodium-Glucose Cotransporter 2 Inhibitors and Pathological Myocardial Hypertrophy.

Zhicheng Gao, Jiaqi Bao, Yilan Hu, Junjie Tu, Lifang Ye, Lihong Wang.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drugs that exert a hypoglycemic effect by blocking the reabsorption of glucose in the proximal renal tubules, thus promoting the excretion of glucose from urine. Their hypoglycemic effect is not dependent on insulin. Increasing data shows that SGLT2 inhibitors improve cardiovascular outcomes in patients with type 2 diabetes. Previous studies have demonstrated that SGLT2 inhibitors can reduce pathological myocardial hypertrophy with or without diabetes, but the exact mechanism remains to be elucidated. To clarify the relationship between SGLT2 inhibitors and pathological myocardial hypertrophy, with a view to providing a reference for the future treatment thereof, this study reviewed the possible mechanisms of SGLT2 inhibitors in attenuating pathological myocardial hypertrophy. We focused specifically on the mechanisms in terms of inflammation, oxidative stress, myocardial fibrosis, mitochondrial function, epicardial lipids, endothelial function, insulin resistance, cardiac hydrogen and sodium exchange, and autophagy.

Keywords: Na+/H+ exchanger; autophagy; epicardial adipose tissue; inflammation; insulin resistance; myocardial fibrosis; myocardial hypertrophy; sodium-glucose cotransporter 2 inhibitors

DOI: https://doi.org/10.2174/1389450124666230907115831

Am J Physiol Cell Physiol. 2023 Sep 11.

Irisin deficiency exacerbates diet-induced insulin resistance and cardiac dysfunction in type II diabetes in mice.

Jianguo Wang, Yu Tina Zhao, Ling Zhang, Patrycja M Dubielecka, Gangjian Qin, Yueh Eugene Chin, Adam C Gower, Shougang Zhuang, Paul Y Liu, Ting C Zhao.

Myokine Irisin is involved in the regulation of a variety of physiological conditions, metabolism, and survival. We and others have demonstrated that recombinant irisin contributes critically to modulation of insulin resistance and the improvement of cardiac function. However, whether deletion of irisin will regulates cardiac function and insulin sensitivity in type II diabetes remains unclear. We utilized the CRISPR/Cas-9 genome-editing system to delete irisin globally in mice and high fat diet (HFD)-induced type II diabetes model. We found that irisin deficiency did not result in developmental abnormality during adult stage, which illustrates normal cardiac function and insulin sensitivity in the absence of stress. The ultrastructural analysis of the transmission electronic microscope (TEM) indicated that deletion of irisin did not change the morphology of mitochondria in myocardium. Gene expression profiling showed that several key signaling pathways related to integrin signaling, extracellular matrix and insulin-like growth factors signaling were coordinately downregulated by deletion of irisin. When mice were fed with a HFD for sixteen weeks, ablation of irisin in mice exposed to HFD resulted in much severer insulin resistance, metabolic derangements, profound cardiac dysfunction and hypertrophic response and remodeling as compared with wild type control. Taken together, our results indicate that the loss of irisin exacerbates insulin resistance, metabolic disorders, and cardiac dysfunction in response to a high fat diet and promoted myocardial remodeling and hypertrophic response. This evidence reveals the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.

Keywords: Cardiac function; Diabetes; Obese; gene expresson; insulin resistance

DOI: https://doi.org/10.1152/ajpcell.00232.2023