Archives of Pharmacy

A brief overview of cardioprotective signaling

2024-10-27T10:28:57+01:00

Cardioprotection is defined as the intrinsic ability of cardiac tissue to withstand challenges like ischemia-reperfusion and different metabolic stresses. Initially observed through ischemic preconditioning, the scope of cardioprotection has expanded to include other inducers of cardioprotective signaling like hypoxia, temperature fluctuations, and many pharmacological agents, suggesting the existence of shared signaling pathways and protective cascades. So far, intracellular signaling factors contributing to cardioprotection include protein kinases, the reperfusion injury salvage kinase (RISK) pathway, the Survivor Activating Factor Enhancement (SAFE) pathway, hypoxia-inducible factor-1α (HIF1α), microRNAs, Connexin 43, and many others. These factors play roles in activating downstream signaling elements and protective genes, enhancing mitochondrial function, and regulating protein expression and cytosolic functions to confer cardioprotection. SUR2A, a regulatory subunit of sarcolemmal ATP-sensitive K⁺ (K_ATP) channels, autophagy and mitochondria are highlighted as crucial end-effectors, with mechanisms like regulation of the mitochondrial permeability transition pore and activation of K_ATP channels being pivotal for cardioprotection. Despite advances in understanding these pathways, many aspects of cardioprotection remain to be better understood. It is a particular challenge to further explore therapeutic potentials and, finally, develop clinically viable strategies for cardiac protection.

KATP channels and cardioprotection

2024-10-27T10:28:58+01:00

This review discusses ATP-sensitive potassium (K_ATP) channels, which connect intracellular energy metabolism to cellular electrical activity and play crucial roles in various physiological processes, particularly in the pancreas and cardiovascular system. K_ATP channels open when ATP levels decrease during metabolic stress, such as ischemia, helping to protect the heart from injury by maintaining membrane potential and preventing calcium overload. These channels are found in multiple cell types across the cardiovascular system, influencing vascular tone and cardiac excitability. The review highlights the need for further research into the specific expression of K_ATP channel subunits in humans and the consequences of ischemic events on their functionality. Additionally, it explores the interplay between glycolysis and K_ATP channels, suggesting that glycolytic ATP can modulate K_ATP channel activity while emphasizing the cardioprotective effects during ischemic events. The potential for K_ATP channel openers (KCOs) as therapeutic agents for ischemic heart disease is noted, particularly in improving outcomes in patients undergoing cardiac procedures. Challenges remain in developing specific KCOs with minimal side effects, but advances in precision medicine may enhance targeted therapies in the future. Overall, K_ATP channels represent promising targets for enhancing cardiovascular health.

Hypoxia-induced cardioprotection: A review

2024-10-27T10:28:59+01:00

Hypoxia, a state of reduced oxygen availability, exerts complex and often paradoxical effects on the heart. While chronic hypoxia is detrimental and leads to adverse cardiac remodeling and dysfunction, short-term or intermittent hypoxia can contribute towards protective adaptations that enhances the heart’s ability to protect itself from ischemic injury. This protective adaptation, also known as hypoxic preconditioning, drives the activation of several essential signaling pathways, including the hypoxia-inducible factor (HIF) signaling, reactive oxygen species (ROS) signaling, nitric oxide (NO) regulation, and ATP-sensitive potassium channel (K_ATP) mediated regulation, leading to metabolic reprogramming, angiogenesis with vascular remodeling, and enhanced calcium handling, thereby increasing resistance to ischemic heart disease. We discuss strategies such as hypoxic conditioning and pharmacologically activated HIF signaling, along with targeted approaches to enhance glycolysis and K_ATP channel regulation and optimize sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) mediated calcium handling in cardiomyocytes. In this review, we explore the mechanisms and therapeutic potential of short-term or intermittent hypoxia-mediated cardioprotection. Additionally, we highlight the importance of addressing challenges and limitations of using hypoxic preconditioning in clinical practice.

Metabolic Modulators in Cardioprotection: A Focus on Trimetazidine

2024-10-27T10:28:59+01:00

Cardiovascular diseases remain a significant health burden worldwide, necessitating the development of effective cardioprotective strategies. Central to this pursuit is the recognition of metabolic dysregulation as a key contributor to the pathogenesis of cardiovascular diseases, particularly in the context of aging and modern lifestyle factors. Metabolic modulators, such as trimetazidine, have emerged as promising therapeutic agents by optimizing cardiac energy substrate utilization and enhancing metabolic efficiency. Trimetazidine demonstrates cardioprotective properties by inhibiting fatty acid oxidation and promoting glucose oxidation, especially under ischemic conditions where oxygen supply is limited. This metabolic shift enhances myocardial efficiency, reduces the likelihood of acidosis, and mitigates the accumulation of toxic fatty acid metabolites. Pre-clinical studies and clinical trials have demonstrated the efficacy of trimetazidine in a range of cardiac conditions, including chronic stable angina, heart failure, and diabetic cardiomyopathy, resulting in improvements in symptoms, exercise capacity, and cardiac function. Through its ability to address underlying metabolic inefficiencies, trimetazidine offers a promising adjunct therapy for patients with cardiovascular diseases, particularly those inadequately controlled by first-line treatments. This manuscript underscores the important role of metabolic modulation in the management of cardiovascular diseases and highlights trimetazidine as a valuable therapeutic option in the armamentarium against cardiac diseases.

Isosteviol: a potential cardioprotective agent

2024-10-27T10:29:00+01:00

Cardioprotection is a term describing the myocardial property to protect itself from injury, particularly in the context of ischemia-reperfusion injury and other metabolic stresses. Recently, isosteviol, a diterpene derived from the hydrolysis of stevioside, a natural sweetener found in the leaves of the Stevia rebaudiana plant, has emerged as a potential cardioprotective compound. In addition to the many therapeutic benefits of isosteviol, including antihyperglycemic, antihypertensive, and anti-inflammatory effects, recent studies have suggested that this compound might have cardioprotective properties as well. It has been demonstrated that isosteviol possesses antioxidant and anti-inflammatory activities, while also regulating ion channels and mitochondrial activity. The cardioprotective effects of isosteviol are mediated through its interaction with multiple signaling pathways. Pre-clinical work has demonstrated that isosteviol regulates NF-κB, phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways, and adenosine monophosphate-activated protein kinase (AMPK), all of which are well-established cardioprotective signaling pathways. All these findings highlight isosteviol's potential as a cardioprotective therapeutic agent. However, this potential needs to be further tested in randomized controlled trials, along with examining isosteviol's possible value in clinical practice, defining optimal dosing strategies, and understanding its long-term effects.

Nicotinamide: A cardioprotective form of Vitamin B3

2024-10-27T10:29:00+01:00

Nicotinamide, a form of vitamin B3, has emerged as a potential cardioprotective agent against ischemia-reperfusion (I/R) injury, a critical factor in the pathogenesis of myocardial infarction, heart failure, and other cardiovascular diseases. This compound plays a significant role in energy metabolism, DNA repair, and cell survival by participating in the biosynthesis of NAD+, a coenzyme essential in redox reactions. The underlying mechanism of cardioprotection afforded by nicotinamide involves enhancing NAD+ biosynthesis, which in turn regulates SUR2A to modulate ATP-sensitive K⁺ (K_ATP) channels, influences sirtuin activity, and affects poly(ADP-ribose) polymerases (PARPs) activity to conserve NAD+ levels. Additionally, nicotinamide exhibits anti-inflammatory properties, regulates autophagy, and exerts antioxidant effects, collectively contributing to its potential to mitigate the impact of I/R injury on the myocardium. Despite its wide range of therapeutic applications and safety profile, distinctions between nicotinamide and another form of vitamin B3 nicotinic acid (niacin) are crucial, especially regarding their effects on lipid profiles and vascular functions. Unlike niacin, nicotinamide does not affect lipid levels or pose a risk of increasing cardiovascular events, highlighting its safety for clinical use at recommended doses. However, so far, no clinical study of nicotinamide in the context of cardioprotection has been done. Randomized controlled trials are clearly needed to examine nicotinamide's possible role in clinical practice, define optimal dosing strategies, and understand its long-term effects. However, considering the history of nicotinamide use, this is a compound that could be quickly introduced in clinical practice for cardioprotection.