Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart

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Abstract

Despite the significant decline in mortality, cardiovascular diseases are still the leading cause of death worldwide. Among them, myocardial infarction (MI) seems to be the most important. A further decline in the death rate may be achieved by the introduction of molecularly targeted drugs. It seems that the components of the PI3K/Akt signaling pathway are good candidates for this. The PI3K/Akt pathway plays a key role in the regulation of the growth and survival of cells, such as cardiomyocytes. In addition, it has been shown that the activation of the PI3K/Akt pathway results in the alleviation of the negative post-infarct changes in the myocardium and is impaired in the state of diabetes. In this article, the role of this pathway was described in each step of ischemia and subsequent left ventricular remodeling. In addition, we point out the most promising substances which need more investigation before introduction into clinical practice. Moreover, we present the impact of diabetes and widely used cardiac and antidiabetic drugs on the PI3K/Akt pathway and discuss the molecular mechanism of its effects on myocardial ischemia and left ventricular remodeling.

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Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Susan A. Elmore (2007)

The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.