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Molecular and cellular mechanisms in diabetic heart failure: Potential therapeutic targets


Review

. 2022 Sep 2;13:947294.


doi: 10.3389/fendo.2022.947294.


eCollection 2022.

Affiliations

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Review

Misganaw Asmamaw Mengstie et al.


Front Endocrinol (Lausanne).


.

Abstract

Diabetes Mellitus (DM) is a worldwide health issue that can lead to a variety of complications. DM is a serious metabolic disorder that causes long-term microvascular and macro-vascular complications, as well as the failure of various organ systems. Diabetes-related cardiovascular diseases (CVD) including heart failure cause significant morbidity and mortality worldwide. Concurrent hypertensive heart disease and/or coronary artery disease have been thought to be the causes of diabetic heart failure in DM patients. However, heart failure is extremely common in DM patients even in the absence of other risk factors such as coronary artery disease and hypertension. The occurrence of diabetes-induced heart failure has recently received a lot of attention. Understanding how diabetes increases the risk of heart failure and how it mediates major cellular and molecular alteration will aid in the development of therapeutics to prevent these changes. Hence, this review aimed to summarize the current knowledge and most recent findings in cellular and molecular mechanisms of diabetes-induced heart failure.


Keywords:

Diabetes Mellitus; Diabetic Heart Failure; heart failure; mechanisms; therapeutic targets.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures



Figure 1

Overview of glucose and fatty acids metabolism in a healthy heart: The glucose transporters GLUT1 and GLUT4 are responsible for glucose uptake into the cardiomyocyte. Once inside the cell, glucose is then phosphorylated to Glucose-6-P. Glucose-6-P is the common intermediate for HMP, HBP, or pyruvate through glycolysis. Pyruvate is then interred to the mitochondria, where it is decarboxylated to acetyl-CoA. Fatty acid transporters (FAT/CD36) transfer non-esterified fatty acids into the cell. Fatty acyl-CoA is formed by intracellular fatty acid activator enzymes and can either be esterified into TAG or reach the mitochondria. Fatty acyl-CoA from mitochondria enters the β-oxidation pathway, where it is converted to acetyl-CoA. Glucose or fatty acid-derived acetyl-CoA enters the TCA cycle, where it undergoes ETC, oxidative phosphorylation, and ATP formation.


Figure 2


Figure 2

Role of mitochondrial dysfunction in diabetic HF. To maintain ATP production, heart cells in DM adapt to enhanced fatty acid oxidation. Concomitantly, the formation of reactive oxygen species (ROS) is also increased, affecting oxidative phosphorylation, damaging mitochondrial DNA, and disturbing Ca2+ homeostasis. Both mitochondrial DNA damage and mPTP opening (due to Ca2+ overload) promote the cardiac apoptotic (programmed cell death) pathway. Through the activation of the cGAS-STING (cyclic GMP-AMP synthase (cGAS) and the cGAS stimulator of interferon genes) pathway, mitochondrial DNA damage may potentially trigger the activation of a pro-inflammatory type of programmed cell death (pyroptosis). Increased mPTP also starts the necroptosis processes. All of which lead to mitochondrial malfunction and ultimately HF.


Figure 3


Figure 3

Outlining the role of ER stress in the development of diabetic HF: Diabetes mellitus raises plasma glucose levels, increases the amount of circulating FFAs, alters cardiac metabolism, and triggers an inflammatory response that activates ERS. When ER function is disrupted, it causes cell autophagy or apoptosis, changes in SERCA protein structure and function, and insulin resistance, which leads to diabetic cardiomyopathy, contractile dysfunction, and eventually heart failure.

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