Figure 3 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Modification of myocardial infarction induced changes in adverse cardiac remodelling and subcellular defects following treatment with ACE (angiotensin converting enzyme) inhibitors. ANG II, angiotensin II.
Source publication
Angiotensin-converting enzyme (ACE) inhibitors, which prevent the conversion of angiotensin I to angiotensin II, are well-known for the treatments of cardiovascular diseases, such as heart failure, hypertension and acute coronary syndrome. Several of these inhibitors including captopril, enalapril, ramipril, zofenopril and imidapril attenuate vasoc...
Context in source publication
Context 1
... ,386 Other beneficial effects of this ACE inhibitor on LV hypertrophy, 387 exercise capacity in chronic heart failure, 388 LV remodeling in acute MI, 389 and subcellular organelle defects have also been reported in failing hearts. 198,[390][391][392][393][394] A schematic representation of the beneficial effects of ACE inhibitors at different subcellular targets for improving heart function and preventing heart failure due to MI is shown in Figure 3. ...
Citations
... [1][2][3][4][5][6][7][8][9][10][11] One of the common components of these signal transducing systems is a group of several protein kinases, which not only transmit the signals to their target sites but also regulate the functions of different subcellular organelles such as sarcolemma, sarcoplasmic reticulum, mitochondria, myofibrils, nucleus and extracellular matrix in the heart. [12][13][14] Several types of protein kinases are present in the myocardium and each of these enzymes have two or more isoforms with some overlapping structural characteristics but distinct biological functions. Some of these signal transducing proteins include protein kinase A (PKA), protein kinase C (PKC), Ca 2+ -calmodulin dependent kinase (CaMK), phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). ...
... [176][177][178][179] It should be also pointed out that prolonged activation of ERK1/2 has been demonstrated to result in the development of heart failure 180,181 and thus antihypertrophic agents such as angiotensin II antagonists and angiotensin converting enzyme inhibitors can be seen to produce beneficial effects in heart failure as a consequence of reduction in the activity of ERK1/2. [12][13][14] It should be noted that both p38-MAPK and JNK are activated by the ischaemic insult 182,183 whereas the effects of ischaemia-reperfusion on ERK1/2 activities are controversial. 184,185 In fact, inhibition of ERK1/2 has been reported to enhance ischaemia-reperfusion injury as well as apoptosis. ...
Various protein kinases including protein kinase A (PKA), Ca2+-calmodulin kinase (CaMK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK: ERK1/2, p38-MAPK and JNK) are integral part of different signal transduction pathways, which are known to regulate cardiac structure, function and metabolism. In addition, these signal transducing proteins are involved in the regulation of cation transport, cellular growth, gene expression, apoptosis and fibrosis by modifying the function of different target sites of subcellular organelles in the myocardium. However, the information regarding these signal transducing molecules is scattered and mechanisms of their involvement in diverse regulatory processes are poorly understood. While PKA, CaMK, PI3K and PKC are activated by different hormones and mechanical stimuli, MAPKs are activated by growth factors and some cellular stresses such as oxidative stress, inflammation and Ca2+-overload. Each type of these protein kinases is expressed in the form of two or more isozymes showing different biochemical characteristics and distinct biological functions. It has been demonstrated that all specific isoforms of these kinases produce both beneficial and detrimental effects on the heart, which are dependent upon the intensity and duration of stimulus for their activation. While PKA, PKC and CaMK are mainly involved in augmenting cardiac function as well as inducing cardiac hypertrophy and arrhythmias, PI3K is mainly involved in maintaining b-adrenoceptor function and inducing inflammation as well as arrhythmias. On the other hand, ERK1/2 mainly participate in the genesis of cardiac hypertrophy and cytoprotection whereas p38-MAPK and JNK are primarily involved in cardiac dysfunction, apoptosis and fibrosis. Since the activities of most protein kinases are increased under prolonged pathological conditions, a wide variety of their inhibitors have been shown to produce beneficial effects. However, extensive research needs to be carried out to understand the pathophysiology of different isoforms of each protein kinase as well as for the development of their isoform-specific inhibitors.
... At early stages, Ang II has been demonstrated to increase blood pressure and produce positive inotropic effect in addition to inducing growth of the myocardium (adaptive cardiac hypertrophy) and promoting angiogenesis [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. However, the exposure of the heart to Ang II for a prolonged period results in the transition of adaptive or physiological cardiac hypertrophy into maladaptive or pathological cardiac hypertrophy, which is considered to serve as a risk factor for the development of heart failure [25][26][27][28][29][30]. Several other vasoactive hormones and different interventions such as pressure overload and volume overload have also been reported to induce both physiological and pathological cardiac hypertrophy [31][32][33][34][35][36][37][38][39][40]. ...
... While the activation of RAS for a short period has been shown to produce adaptive cardiac hypertrophy for maintaining cardiovascular function, prolonged activation of RAS or exposure of the heart to Ang II for a prolonged period is known to result in maladaptive cardiac hypertrophy, a well-known risk factor for heart failure [3,4,16,20,26,57]. It should be noted that besides Ang II, different other biologically active peptides such as Ang-(2-8) (Ang III), Ang-(3-8) (Ang IV) and Ang-(1-7) have been shown to exert dramatic effects on the cardiovascular system [9,27]. Furthermore, Ang II-induced actions such as vasoconstriction, cardiac hypertrophy, inflammation, oxidative stress, fibrosis and fluid retention are mediated through Ang II type I receptors (AT 1 R) whereas the effects of Ang-(1-7) are elicited by the activation of Mas receptors [19,25,54,58]. ...
... It should be pointed out that under pathological conditions, the activation of circulating RAS by a fall in blood pressure is associated with a release of angiotensinogen from the kidney, which is then converted into Ang I by the action of renin (present in the liver). It has also been demonstrated that angiotensin-converting enzyme (ACE) is involved in the conversion of Ang I to Ang II, Ang III and Ang IV in the lung whereas a homologue of ACE (ACE2) converts Ang I to Ang (1-9) as well as Ang II into Ang (1-7) [7,27]. On the other hand, it has been shown that all these compounds of circulating RAS are present in the local RAS (in various organs), which is activated mainly by an increase in ventricular wall stress [8][9][10]. ...
Although acute exposure of the heart to angiotensin (Ang II) produces physiological cardiac hypertrophy and chronic exposure results in pathological hypertrophy, the signal transduction mechanisms for these effects are of complex nature. It is now evident that the hypertrophic response is mediated by the activation of Ang type 1 receptors (AT1R), whereas the activation of Ang type 2 receptors (AT2R) by Ang II and Mas receptors by Ang-(1-7) exerts antihypertrophic effects. Furthermore, AT1R-induced activation of phospholipase C for stimulating protein kinase C, influx of Ca2+ through sarcolemmal Ca2+- channels, release of Ca2+ from the sarcoplasmic reticulum, and activation of sarcolemmal NADPH oxidase 2 for altering cardiomyocytes redox status may be involved in physiological hypertrophy. On the other hand, reduction in the expression of AT2R and Mas receptors, the release of growth factors from fibroblasts for the occurrence of fibrosis, and the development of oxidative stress due to activation of mitochondria NADPH oxidase 4 as well as the depression of nuclear factor erythroid-2 activity for the occurrence of Ca2+-overload and activation of calcineurin may be involved in inducing pathological cardiac hypertrophy. These observations support the view that inhibition of AT1R or activation of AT2R and Mas receptors as well as depression of oxidative stress may prevent or reverse the Ang II-induced cardiac hypertrophy.
Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably preceded by adaptive or maladaptive cardiac hypertrophy, several biochemical mechanisms have been proposed to explain the development of cardiac hypertrophy and progression to heart failure. One of these includes the activation of different neuroendocrine systems for elevating the circulating levels of different vasoactive hormones such as catecholamines, angiotensin II, vasopressin, serotonin and endothelins. All these hormones are released in the circulation and stimulate different signal transduction systems by acting on their respective receptors on the cell membrane to promote protein synthesis in cardiomyocytes and induce cardiac hypertrophy. The elevated levels of these vasoactive hormones induce hemodynamic overload, increase ventricular wall tension, increase protein synthesis and the occurrence of cardiac remodeling. In addition, there occurs an increase in proinflammatory cytokines and collagen synthesis for the induction of myocardial fibrosis and the transition of adaptive to maladaptive hypertrophy. The prolonged exposure of the hypertrophied heart to these vasoactive hormones has been reported to result in the oxidation of catecholamines and serotonin via monoamine oxidase as well as the activation of NADPH oxidase via angiotensin II and endothelins to promote oxidative stress. The development of oxidative stress produces subcellular defects, Ca2+-handling abnormalities, mitochondrial Ca2+-overload and cardiac dysfunction by activating different proteases and depressing cardiac gene expression, in addition to destabilizing the extracellular matrix upon activating some metalloproteinases. These observations support the view that elevated levels of various vasoactive hormones, by producing hemodynamic overload and activating their respective receptor-mediated signal transduction mechanisms, induce cardiac hypertrophy. Furthermore, the occurrence of oxidative stress due to the prolonged exposure of the hypertrophied heart to these hormones plays a critical role in the progression of heart failure.
An increase in the occurrence of different infectious and chronic diseases as well as aging population has resulted in poor human health and decline in the quality of life all over the world. In fact, chronic diseases, which are partially resistant to currently available drugs are long lasting health hazards and require ongoing medical attention. Major causes of increase in these diseases are considered to be changes in the environment as well as diets and lifestyle. Particularly, there has been changes from a simple, nutritious, lowcalorie diet and active lifestyle to a complex and processed food rich in high calories accompanied by a sedentary lifestyle and unhealthy living habits. Since high-calorie diets and inactive lifestyle are known to promote the production of reactive oxygen species (ROS) in the body, it is likely that oxidative stress and associated inflammation may be intimately involved in enhancing the resistance of several disorders to the existing therapeutic interventions and thus promoting the occurrence of chronic diseases. A thorough review of literature regarding the pathogenesis of some major chronic diseases including cardiovascular disease like heart failure, neurodegenerative disorder like Alzheimer's disease and various types of cancer has revealed that these health hazards are associated with increased oxidative stress, production of pro-inflammatory chemicals such as nitric oxide and some cytokines, as well as formation of some toxic substances such as advanced glycation end products. It is thus evident that extensive research work by employing genetic, immunological and nutraceutical approaches, needs to be carried out for developing some novel antioxidants with anti-inflammatory activities for reducing the incidence of chronic diseases. In the meantime, it would be prudent for patients with chronic diseases to pursue the preventive measures involving reduced intake of high calorie diet and following an active lifestyle
Background: The prevention of drug-induced cardiotoxicity is a complicated challenge facing healthcare providers during the last few decades. This challenge is raised from the unclear definition of the term “cardiotoxicity”, the overlapping of the symptoms of heart dysfunction due to the underlying diseases and the used drugs or using a combination of drugs which makes it difficult to distinguish between the side effects of each drug. Objective: This review discusses the most causative agents of cardiotoxicity, and their mechanisms to induce cardiac muscle damage, and finally focuses on the most applicable methods to deal with these dangerous heart problems. Methods: The search method involved electronic databases, including PubMed, Web of Science, Springer, Google Scholar, and others to resume relevant trials of heart disease published in the period between 2010-2023. Conclusion: Cardiotoxicity is a common substantial adverse effect of many drugs including anticancer drugs and others. The prevention methods may include medications, such as (Enalapril or carvedilol), supplementation with antioxidants, or cardioprotective natural products.
The renin-angiotensin system (RAS) is one of major neuro-endocrine entity which is intimately involved in regulating the cellular functions and metabolic activities in the body. The activation of RAS results in the formation and release of angiotensin II mainly as well as angiotensin 1–7 through the participation of angiotensin converting enzyme (ACE) and its homolog ACE2, respectively. Angiotensin II upon activating the angiotensin type 1 receptors (AT1R) is known to produce a wide variety of effects namely vasoconstriction, fluid retention, fibrosis and thrombosis in addition to promoting oxidative stress, inflammation and hypertrophic process. On the other hand, angiotensin II by activating the angiotensin type 2 receptors (AT2R) produces effects which are antagonists to those due to AT1R activation. Furthermore, angiotensin 1–7 has been shown to activate Mas receptors and exert actions which are similar to those for AT2R activation but antagonists to those for AT1R activation. The effects of AT1R activation during initial stages of pathological stimulus are considered to be of adaptive nature for maintaining homeostasis in all organs but over a prolonged period it is known to produce adverse effects which are associated with the development of diverse diseases. Although the activation of both AT2R and Mas receptor is antagonistic to AT1R activation, the exact role of these receptor systems at different stages of disease progression and organ dysfunction remains to be investigated.KeywordsPeripheral RASLocal RASAngiotensin IIAT1R activationAT2R activationMas receptorsAngiotensin converting enzymes
