Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities

Tuleta, Izabela; Frangogiannis, Nikolaos G.

doi:10.1016/j.addr.2021.113904

Cited by 68 publications

(51 citation statements)

References 478 publications

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“…The current study found that continuous KD feeding increased the levels of circulating lipids, as well as hepatic lipid deposition, in TAC mice, suggesting systemic fatty acid metabolic disorder. Fatty acid metabolic disorder is a risk factor of various diseases, including cardiovascular disease [ 36 – 38 ]. Thus, the capacity of the body to maintain lipid homeostasis is important in the biological effects of KD feeding.…”

Section: Discussionmentioning

confidence: 99%

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

Guo¹,

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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As heart failure develops, the heart utilizes ketone bodies at increased rates, indicating an adaptive stress response. Thus, increasing ketone body availability exerts protective effects against heart failure. However, although it is the widely used approach for increasing ketone body availability, the ketogenic diet shows limited cardioprotective effects against heart failure. This study was aimed at examining the effects of the ketogenic diet on heart failure and the underlying mechanisms. Pressure overload-induced heart failure was established by transverse aortic constriction (TAC) in mice. Continuous ketogenic diet feeding for 8 weeks failed to protect the heart against heart failure. It showed no significant effects on cardiac systolic function and fibrosis but aggravated cardiac diastolic function in TAC mice. Specifically, it induced systemic lipid metabolic disorder and hepatic dysfunction in TAC mice. It decreased the content of 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), a key enzyme in ketogenesis, and impaired the capacity of hepatic ketogenesis in TAC mice. It preserved the capacity of hepatic ketogenesis and exerted cardioprotective effects against heart failure, increasing cardiac function and decreasing cardiac fibrosis, in liver-specific HMGCL-overexpressed TAC mice. Importantly, we found that alternate-day ketogenic diet feeding did not impair the capacity of hepatic ketogenesis and exerted potent cardioprotective effects against heart failure. These results suggested that alternate-day but not continuous ketogenic diet protects against heart failure through preservation of ketogenesis in the liver.

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Section: Discussionmentioning

confidence: 99%

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

Guo¹,

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Existing studies have suggested that tissue inflammation, oxidative stress, and dysregulation of autophagy induced by high-glucose stimulation can promote dysfunction of cardiomyocytes and fibrosis of the myocardial interstitium, thus leading to diabetic cardiomyopathy [ 37 , 38 ]. Myocardial fibrosis is a vital pathological change leading to diabetic cardiomyopathy, which is primarily manifested as myocardial pathological changes characterized by excessive deposition of myocardial extracellular matrix and myocardial structural disorder; it can develop into heart failure [ 39 - 41 ]. In this experiment, a model of rats with type II diabetes was established by a diet high in fat and sugar and through the intraperitoneal injection of STZ.…”

Section: Discussionmentioning

confidence: 99%

Gaseous signal molecule SO₂ regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

Zhao

Yang

et al. 2022

Korean J Physiol Pharmacol

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Myocardial fibrosis is a key link in the occurrence and development of diabetic cardiomyopathy. Its etiology is complex, and the effect of drugs is not good. Cardiomyocyte apoptosis is an important cause of myocardial fibrosis. The purpose of this study was to investigate the effect of gaseous signal molecule sulfur dioxide (SO 2 ) on diabetic myocardial fibrosis and its internal regulatory mechanism. Masson and TUNEL staining, Western-blot, transmission electron microscopy, RT-qPCR, immunofluorescence staining, and flow cytometry were used in the study, and the interstitial collagen deposition, autophagy, apoptosis, and changes in phosphatidylinositol 3-kinase (PI3K)/AKT pathways were evaluated from in vivo and in vitro experiments. The results showed that diabetic myocardial fibrosis was accompanied by cardiomyocyte apoptosis and down-regulation of endogenous SO 2 -producing enzyme aspartate aminotransferase (AAT) 1/2 . However, exogenous SO 2 donors could up-regulate AAT 1/2 , reduce apoptosis of cardiomyocytes induced by diabetic rats or high glucose, inhibit phosphorylation of PI3K/AKT protein, up-regulate autophagy, and reduce interstitial collagen deposition. In conclusion, the results of this study suggest that the gaseous signal molecule SO 2 can inhibit the PI3K/AKT pathway to promote cytoprotective autophagy and inhibit cardiomyocyte apoptosis to improve myocardial fibrosis in diabetic rats. The results of this study are expected to provide new targets and intervention strategies for the prevention and treatment of diabetic cardiomyopathy.

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“…However, DCM is a complicated process involving multiple mechanisms except EndMT and myocardial fibrosis. A previous study has shown that the decrease of blood glucose may partly play a role in reducing the myocardial collagen deposition in the treatment of diabetes, but it is not clear whether lowering blood glucose can affect myocardial fibrosis and myocardial dysfunction ( Tuleta and Frangogiannis, 2021 ). The development of DCM involves a variety of mechanisms of decisive molecular, cellular and interstitial changes, including myocardial energy substrate imbalance, glucose and lipid toxicity, insulin signal changes, mitochondrial defects, endoplasmic reticulum (ER) stress, intracellular calcium processing disorder, oxidative stress, endothelial dysfunction, advanced glycation end products (AGEs) deposition, and maladaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway

et al. 2021

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Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus, which is associated with fibrosis and microRNAs (miRs). This study estimated the mechanism of miR-195-5p in endothelial mesenchymal transition (EndMT) and myocardial fibrosis in DCM. After the establishment of DCM rat models, miR-195-5p was silenced by miR-195-5p antagomir. The cardiac function-related indexes diastolic left ventricular anterior wall (LVAW, d), systolic LVAW (d), diastolic left ventricular posterior wall (LVPW, d), systolic LVPW (d), left ventricular ejection fraction (LVEF), and fractional shortening (FS) were measured and miR-195-5p expression in myocardial tissue was detected. Myocardial fibrosis, collagen deposition, and levels of fibrosis markers were detected. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (HG) and miR-195-5p was silenced. The levels of fibrosis proteins, endothelial markers, fibrosis markers, EndMT markers, and transforming growth factor beta 1 (TGF-β1)/Smads pathway-related proteins were measured in HUVECs. The interaction between miR-195-5p and Smad7 was verified. In vivo, miR-195-5p was highly expressed in the myocardium of DCM rats. Diastolic and systolic LVAW, diastolic and systolic LVPW were increased and LVEF and FS were decreased. Inhibition of miR-195-5p reduced cardiac dysfunction, myocardial fibrosis, collagen deposition, and EndMT, promoted CD31 and VE-cadehrin expressions, and inhibited α-SMA and vimentin expressions. In vitro, HG-induced high expression of miR-195-5p and the expression changes of endothelial markers CD31, VE-cadehrin and fibrosis markers α-SMA and vimentin were consistent with those in vivo after silencing miR-195-5p. In mechanism, miR-195-5p downregulation blocked EndMT by inhibiting TGF-β1-smads pathway. Smad7 was the direct target of miR-195-5p and silencing miR-195-5p inhibited EndMT by promoting Smad7 expression. Collectively, silencing miR-195-5p inhibits TGF-β1-smads-snail pathway by targeting Smad7, thus inhibiting EndMT and alleviating myocardial fibrosis in DCM.

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Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities

Cited by 68 publications

References 478 publications

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

Gaseous signal molecule SO₂ regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway

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Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities

Cited by 68 publications

References 478 publications

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

Gaseous signal molecule SO2 regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway

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Gaseous signal molecule SO₂ regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes