MicroRNAs and Cardiovascular Health: Unraveling Their Roles in Oxidative Stress

Medical News: MicroRNAs (miRNAs) have emerged as pivotal regulators in various diseases, including cardiovascular diseases (CVDs). These tiny non-coding RNAs play significant roles in gene expression, influencing disease development and progression. In parallel, reactive oxygen species (ROS) and oxidative stress are well-known contributors to CVDs. This Medical News report explores the intricate relationship between miRNAs and oxidative stress in the context of cardiovascular health.


MicroRNAs and Cardiovascular Health: Unraveling Their
Roles in Oxidative Stress

Cardiovascular Diseases and Oxidative Stress
Cardiovascular diseases, including ischemic heart disease, stroke, and hypertension, are leading causes of mortality worldwide. In 2021 alone, they accounted for approximately 14.72 million deaths globally. The development and progression of CVDs are influenced by various factors, including hypertension, high cholesterol, smoking, diabetes, obesity, and notably, oxidative stress.
 
Oxidative stress results from an imbalance between ROS production and the body's ability to detoxify these reactive intermediates. ROS, including superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide, are byproducts of normal cellular metabolism. While ROS play roles in cell signaling and defense, their excessive accumulation can damage cellular components, contributing to CVDs.
 
The Role of Antioxidants
To counteract oxidative stress, cells are equipped with antioxidant systems, comprising enzymatic and non-enzymatic components. Enzymatic antioxidants like superoxide dismutases (SODs), catalase, and glutathione peroxidase (GPx) detoxify ROS. Non-enzymatic antioxidants, including glutathione, vitamin C, and vitamin E, also play crucial roles in maintaining cellular redox balance.
 
MicroRNAs: Tiny Regulators with Big Impacts
MiRNAs are short, non-coding RNAs that regulate gene expression by binding to messenger RNAs (mRNAs) and inhibiting their translation or promoting their degradation. Over 60% of mammalian mRNAs are regulated by miRNAs, highlighting their importance in cellular processes.

In the cardiovascular system, miRNAs are involved in various aspects of heart function and pathology. Dysregulation of specific miRNAs has been implicated in conditions like heart failure, myocardial infarction, and hypertension.
 
miRNAs and Oxidative Stress in Cardiovascular Diseases
Given the roles of both ROS and miRNAs in CVDs, it is not surprising that these two entities interact closely. This section delves into specific miRNAs that regulate oxidative stress in the cardiovascular system.
 
Up-regulated miRNAs in CVDs
-miR-15
MiR-15 is significantly up-regulated in infarcted cardiac tissue following ischemia/reperfusion (I/R) injury. Its suppression reduces infarct size and enhances cardiac function. MiR-15b, a member o f the miR-15 family, targets sirtuin 4 (SIRT4), which plays a role in mitochondrial ROS production. Overexpression of SIRT4 increases ROS production, suggesting that miR-15b may contribute to oxidative stress regulation by modulating SIRT4.
 
-miR-17-92 Cluster
The miR-17-92 cluster includes miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1. This cluster is up-regulated in chronic hypoxia-induced pulmonary artery hypertension (PAH) and hypertrophic cardiomyopathy (HCM). MiR-92a targets heme oxygenase 1 (HO-1), an enzyme with antioxidant properties. The inhibition of miR-92a preserves endothelial function by maintaining HO-1 production and suppressing oxidative stress.
 
-miR-21
MiR-21 is up-regulated in conditions like arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM). It plays a protective role in myocardial I/R injury by suppressing apoptosis and remodeling. However, its role in ROS regulation remains elusive, with some studies suggesting it may facilitate antioxidant responses while others indicate it promotes ROS accumulation.
 
-miR-22
MiR-22 is abundant in cardiac tissue and is up-regulated in cardiac hypertrophy models. It targets SIRT1 and PGC-1α, both involved in oxidative stress regulation. While miR-22 promotes SIRT1 expression, it suppresses PGC-1α, suggesting a complex role in balancing ROS production and antioxidant defenses.
 
-miR-23
MiR-23 is up-regulated in myocardial infarction (MI) and I/R injury models. It targets peroxisome proliferator-activated receptor alpha (PPARα), a regulator of antioxidant genes. Suppression of miR-23 or overexpression of PPARα increases antioxidant gene expression, suggesting miR-23 may contribute to oxidative stress in CVDs.
 
Down-regulated miRNAs in CVDs
-miR-129
MiR-129 is down-regulated in chronic heart failure (CHF) and myocardial I/R injury models. It targets Keap1, a negative regulator of Nrf2, and HMGB1, which modulates NADPH oxidase (NOX) activity. Down-regulation of Keap1 enhances Nrf2-dependent antioxidant gene expression, while suppression of HMGB1 reduces NOX-mediated ROS production.
 
-miR-130
MiR-130 is down-regulated in cardiac fibroblasts (cFBs) exposed to hypoxia and MI models. It targets HMGB2, similar to HMGB1, and regulates the Nrf2/HO-1 signaling pathway. Maintaining miR-130 levels can be cardioprotective by enhancing antioxidant defenses.
 
-miR-133
MiR-133 is down-regulated in MI patients and hypoxic conditions. It targets BACH1, a transcriptional repressor of Nrf2. Down-regulation of miR-133 increases BACH1 levels, suppressing Nrf2-dependent antioxidant gene expression and contributing to oxidative stress.
 
-miR-142
MiR-142 is down-regulated in cardiac hypertrophy and MI models. It targets HMGB1, which activates NOX and increases ROS production. Down-regulation of miR-142 may contribute to oxidative stress in the cardiovascular system.
 
-miR-148
MiR-148 is down-regulated in myocardial I/R injury and atherosclerosis. It targets PDK4, involved in ROS production, and SESN2, which activates Nrf2 signaling. The dual roles of miR-148 in targeting both pro-oxidative and antioxidant pathways highlight its complex impact on oxidative stress.
 
Varied miRNAs in CVDs
-miR-1
MiR-1 expression varies in different CVD models. It targets several antioxidant genes, including SOD1, GCLC, and G6PD. The variability in miR-1 expression across studies suggests species-dependent differences or sensitivity to experimental conditions.
 
-miR-103
MiR-103 shows inconsistent expression patterns in CVD models. It targets BNIP3, involved in ROS production and mitophagy. The regulation of BNIP3 by miR-103 highlights its role in maintaining mitochondrial health and oxidative stress balance.
 
-miR-132
MiR-132 expression varies depending on the type of CVD. It targets FOXO3a, SIRT1, and PTEN, all involved in antioxidant responses. The complex regulation of miR-132 underscores its multifaceted role in oxidative stress and cardiovascular health.
 
-miR-206
MiR-206 shows variable expression in MI and H/R injury models. It targets SOD1, a key antioxidant enzyme. The regulation of SOD1 by miR-206 suggests its role in modulating ROS levels in the cardiovascular system.
 
-miR-214
MiR-214 is up-regulated in various CVD models, including MI and cardiac hypertrophy. It targets ME2 and GSR, both involved in ROS regulation. The dual targeting by miR-214 highlights its potential to influence oxidative stress and antioxidant defenses.
 
Conclusion
The intricate interplay between miRNAs and oxidative stress plays a crucial role in the development and progression of cardiovascular diseases. Understanding these interactions can pave the way for novel diagnostic and therapeutic strategies. While significant progress has been made, further research is essential to unravel the complex regulatory networks involving miRNAs and oxidative stress in cardiovascular health. By elucidating these mechanisms, we can better understand and combat the burden of cardiovascular diseases.
 
The study findings were published in the peer reviewed journal:
https://www.mdpi.com/2076-3921/13/6/656
 
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https://www.thailandmedical.news/news/thailand-medical-news-exclusive-deciphering-the-intricate-role-of-mirnas-in-heart-disorders-in-covid-19