Metabolomics Profiling of Stages of Coronary Artery Disease Progression.

Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression. Hypercholesterolemia (HC), hypertension (HT), and diabetes are key contributors to CAD development. Metabolomics, with its comprehensive analysis of metabolites, offers a unique perspective on cardiovascular diseases. This study leveraged metabolomics profiling to investigate the progression of CAD, focusing on the interplay of hypercholesterolemia, hypertension, and diabetes. We performed a metabolomic analysis on 221 participants from four different groups: (I) healthy individuals, (II) individuals with hypercholesterolemia (HC), (III) individuals with both HC and hypertension (HT) or diabetes, and (IV) patients with self-reported coronary artery disease (CAD). Utilizing data from the Qatar Biobank, we combined clinical information, metabolomic profiling, and statistical analyses to identify key metabolites associated with CAD risk. Our data identified distinct metabolite profiles across the study groups, indicating changes in carbohydrate and lipid metabolism linked to CAD risk. Specifically, levels of mannitol/sorbitol, mannose, glucose, and ribitol increased, while pregnenediol sulfate, oleoylcarnitine, and quinolinate decreased with higher CAD risk. These findings suggest a significant role of sugar, steroid, and fatty acid metabolism in CAD progression and point to the need for further research on the correlation between quinolinate levels and CAD risk, potentially guiding targeted treatments for atherosclerosis. This study provides novel insights into the metabolomic changes associated with CAD progression, emphasizing the potential of metabolites as predictive biomarkers.

Proteomic Analysis of Prehypertensive and Hypertensive Patients: Exploring the Role of the Actin Cytoskeleton.

Hypertension is a pervasive and widespread health condition that poses a significant risk factor for cardiovascular disease, which includes conditions such as heart attack, stroke, and heart failure. Despite its widespread occurrence, the exact cause of hypertension remains unknown, and the mechanisms underlying the progression from prehypertension to hypertension require further investigation. Recent proteomic studies have shown promising results in uncovering potential biomarkers related to disease development. In this study, serum proteomic data collected from Qatar Biobank were analyzed to identify altered protein expression between individuals with normal blood pressure, prehypertension, and hypertension and to elucidate the biological pathways contributing to this disease. The results revealed a cluster of proteins, including the SRC family, CAMK2B, CAMK2D, TEC, GSK3, VAV, and RAC, which were markedly upregulated in patients with hypertension compared to those with prehypertension (fold change ≥ 1.6 or ≤-1.6, area under the curve ≥ 0.8, and q-value < 0.05). Pathway analysis showed that the majority of these proteins play a role in actin cytoskeleton remodeling. Actin cytoskeleton reorganization affects various biological processes that contribute to the maintenance of blood pressure, including vascular tone, endothelial function, cellular signaling, inflammation, fibrosis, and mechanosensing. Therefore, the findings of this study suggest a potential novel role of actin cytoskeleton-related proteins in the progression from prehypertension to hypertension. The present study sheds light on the underlying pathological mechanisms involved in hypertension and could pave the way for new diagnostic and therapeutic approaches for the treatment of this disease.

Metabolomic profiling reveals key metabolites associated with hypertension progression.

Introduction: Pre-hypertension is a prevalent condition among the adult population worldwide. It is characterized by asymptomatic elevations in blood pressure beyond normal levels but not yet reaching the threshold for hypertension. If left uncontrolled, pre-hypertension can progress to hypertension, thereby increasing the risk of serious complications such as heart disease, stroke, kidney damage, and others. Objective: The precise mechanisms driving the progression of hypertension remain unknown. Thus, identifying the metabolic changes associated with this condition can provide valuable insights into potential markers or pathways implicated in the development of hypertension. Methods: In this study, we utilized untargeted metabolomics profiling, which examines over 1,000 metabolites to identify novel metabolites contributing to the progression from pre-hypertension to hypertension. Data were collected from 323 participants through Qatar Biobank. Results: By comparing metabolic profiles between pre-hypertensive, hypertensive and normotensive individuals, six metabolites including stearidonate, hexadecadienoate, N6-carbamoylthreonyladenosine, 9 and 13-S-hydroxyoctadecadienoic acid (HODE), 2,3-dihydroxy-5-methylthio- 4-pentenoate (DMTPA), and linolenate were found to be associated with increased risk of hypertension, in both discovery and validation cohorts. Moreover, these metabolites showed a significant diagnostic performance with area under curve >0.7. Conclusion: These findings suggest possible biomarkers that can predict the risk of progression from pre-hypertension to hypertension. This will aid in early detection, diagnosis, and management of this disease as well as its associated complications.

Between Inflammation and Autophagy: The Role of Leptin-Adiponectin Axis in Cardiac Remodeling.

Cardiac remodeling is the process by which the heart adapts to stressful stimuli, such as hypertension and ischemia/reperfusion; it ultimately leads to heart failure upon long-term exposure. Autophagy, a cellular catabolic process that was originally considered as a mechanism of cell death in response to detrimental stimuli, is thought to be one of the main mechanisms that controls cardiac remodeling and induces heart failure. Dysregulation of the adipokines leptin and adiponectin, which plays essential roles in lipid and glucose metabolism, and in the pathophysiology of the neuroendocrine and cardiovascular systems, has been shown to affect the autophagic response in the heart and to contribute to accelerate cardiac remodeling. The obesity-associated protein leptin is a pro-inflammatory, tumor-promoting adipocytokine whose elevated levels in obesity are associated with acute cardiovascular events, and obesity-related hypertension. Adiponectin exerts anti-inflammatory and anti-tumor effects, and its reduced levels in obesity correlate with the pathogenesis of obesity-associated cardiovascular diseases. Leptin- and adiponectin-induced changes in autophagic flux have been linked to cardiac remodeling and heart failure. In this review, we describe the different molecular mechanisms of hyperleptinemia- and hypoadiponectinemia-mediated pathogenesis of cardiac remodeling and the involvement of autophagy in this process. A better understanding of the roles of leptin, adiponectin, and autophagy in cardiac functions and remodeling, and the exact signal transduction pathways by which they contribute to cardiac diseases may well lead to discovery of new therapeutic agents for the treatment of cardiovascular remodeling.

Effect of Flow-Induced Shear Stress in Nanomaterial Uptake by Cells: Focus on Targeted Anti-Cancer Therapy.

Recently, nanomedicines have gained a great deal of attention in diverse biomedical applications, including anti-cancer therapy. Being different from normal tissue, the biophysical microenvironment of tumor cells and cancer cell mechanics should be considered for the development of nanostructures as anti-cancer agents. Throughout the last decades, many efforts devoted to investigating the distinct cancer environment and understanding the interactions between tumor cells and have been applied bio-nanomaterials. This review highlights the microenvironment of cancer cells and how it is different from that of healthy tissue. We gave special emphasis to the physiological shear stresses existing in the cancerous surroundings, since these stresses have a profound effect on cancer cell/nanoparticle interaction. Finally, this study reviews relevant examples of investigations aimed at clarifying the cellular nanoparticle uptake behavior under both static and dynamic conditions.

Molecular Mechanisms of Adiponectin-Induced Attenuation of Mechanical Stretch-Mediated Vascular Remodeling.

Hypertension induces vascular hypertrophy, which changes blood vessels structurally and functionally, leading to reduced tissue perfusion and further hypertension. It is also associated with dysregulated levels of the circulating adipokines leptin and adiponectin (APN). Leptin is an obesity-associated hormone that promotes vascular smooth muscle cell (VSMC) hypertrophy. APN is a cardioprotective hormone that has been shown to attenuate hypertrophic cardiomyopathy. In this study, we investigated the molecular mechanisms of hypertension-induced VSMC remodeling and the involvement of leptin and APN in this process. To mimic hypertension, the rat portal vein (RPV) was mechanically stretched, and the protective effects of APN on mechanical stretch-induced vascular remodeling and the molecular mechanisms involved were examined by using 10 µg/ml APN. Mechanically stretching the RPV significantly decreased APN protein expression after 24 hours and APN mRNA expression in a time-dependent manner in VSMCs. The mRNA expression of the APN receptors AdipoR1, AdipoR2, and T-cadherin significantly increased after 15 hours of stretch. The ratio of APN/leptin expression in VSMCs significantly decreased after 24 hours of mechanical stretch. Stretching the RPV for 3 days increased the weight and [3H]-leucine incorporation significantly, whereas APN significantly reduced hypertrophy in mechanically stretched vessels. Stretching the RPV for 10 minutes significantly decreased phosphorylation of LKB1, AMPK, and eNOS, while APN significantly increased p-LKB1, p-AMPK, and p-eNOS in stretched vessels. Mechanical stretch significantly increased p-ERK1/2 after 10 minutes, whereas APN significantly reduced stretch-induced ERK1/2 phosphorylation. Stretching the RPV also significantly increased ROS generation after 1 hour, whereas APN significantly decreased mechanical stretch-induced ROS production. Exogenous leptin (3.1 nM) markedly increased GATA-4 nuclear translocation in VSMCs, whereas APN significantly attenuated leptin-induced GATA-4 nuclear translocation. Our results decipher molecular mechanisms of APN-induced attenuation of mechanical stretch-mediated vascular hypertrophy, with the promising potential of ultimately translating this protective hormone into the clinic.