Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

Signal transducer and activator of transcription 3 (STAT3) protects the heart from acute ischemic stress. However, the importance of STAT3 to the heart in chronic stress, such as hypertension, is not known. To study this, we used cardiomyocyte-targeted STAT3 knockout (KO) mice and ANG II infusion by osmotic minipumps. After 4 weeks, ANG II induced similar cardiac hypertrophy in wild type (WT) and cardiac Cre-expressing control (CTRL) mice with no impairment of cardiac function. In contrast, STAT3 KO mice exhibited reduced contractile function but similar hypertrophy to CTRL mice. Ejection fraction and fractional shortening decreased by 22.5% and 27.3%, respectively. Since STAT3 has direct protective effects on mitochondrial function, we examined rates of glucose and oleate oxidation by isolated perfused hearts using a Langendorff system. Hearts of ANG II-treated STAT3 KO and CTRL mice had similar rates of oleate oxidation as saline-infused WT mice. Rates of glucose oxidation were similar between hearts of WT plus saline and CTRL plus ANG II mice; however, glucose oxidation was increased by 66% in hearts of ANG II-treated STAT3 KO mice. The ratio of maximal ATP yield from glucose to fatty acid oxidation was 21.1 ± 3.1 in hearts of ANG II-treated STAT3 KO mice vs. 12.6 ± 2.2 in hearts of ANG II-treated CTRL mice. Lactate production was also elevated in hearts of ANG II-treated STAT3 KO mice by 162% compared to ANG II-treated CTRL mice. Our findings indicate that (1) STAT3 is important for maintaining contractile function and metabolic homeostasis in the hypertensive heart, and (2) STAT3 deficiency promotes a switch toward glucose utilization

The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart.

Accumulating evidence reveals involvement of T lymphocytes and adaptive immunity in the chronic inflammation associated with infectious and noninfectious diseases of the heart, including coronary artery disease, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, hypertensive left ventricular (LV) hypertrophy, and nonischemic heart failure. Chemokine CXCL10 is elevated in cardiovascular diseases, along with increased cardiac infiltration of proinflammatory Th1 and cytotoxic T cells. CXCL10 is a chemoattractant for these T cells and polarizing factor for the proinflammatory phenotype. Thus, targeting the CXCL10 receptor CXCR3 is a promising therapeutic approach to treating cardiac inflammation. Due to biased signaling CXCR3 also couples to anti-inflammatory signaling and immunosuppressive regulatory T cell formation when activated by CXCL11. Numbers and functionality of regulatory T cells are reduced in patients with cardiac inflammation, supporting the utility of biased agonists or biologicals to simultaneously block the pro-inflammatory and activate the anti-inflammatory actions of CXCR3. Other immunotherapy strategies to boost regulatory T cell actions include intravenous immunoglobulin (IVIG) therapy, adoptive transfer, immunoadsorption, and low-dose interleukin-2/interleukin-2 antibody complexes. Pharmacological approaches include sphingosine 1-phosphate receptor 1 agonists and vitamin D supplementation. A combined strategy of switching CXCR3 signaling from pro- to anti-inflammatory and improving Treg functionality is predicted to synergistically lessen adverse cardiac remodeling

Conflicting vascular and metabolic impact of the IL-33/sST2 axis.

Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases

STAT3 and Endothelial Cell—Cardiomyocyte Dialog in Cardiac Remodeling

This article presents an overview of the central role of STAT3 in the crosstalk between endothelial cells and cardiac myocytes in the heart. Endothelial cell STAT3 has a key role in inflammation that underlies cardiovascular disease and impacts on cardiac structure and function. STAT3 in endothelial cells contributes to adverse cardiomyocyte genetic reprograming, for instance, during peripartum cardiomyopathy. Conversely, cardiomyocyte STAT3 is important for maintaining endothelial cell function and capillary integrity with aging and hypertension. In addition, STAT3 serves as a sentinel for stress in the heart. Recent evidence has revealed that the redox nature of STAT3 is regulated, and STAT3 is responsive to oxidative stress (ischemia-reperfusion) so as to induce protective genes. At the level of the mitochondrion, STAT3 is important in regulating reactive oxygen species (ROS) formation, metabolism, and mitochondrial integrity. STAT3 may also control calcium release from the ER so as to limit its subsequent uptake by mitochondria and the induction of cell death. Under normal conditions, some STAT3 localizes to intercalated discs of cardiomyocytes and serves to transmit pro-fibrotic gene induction signals in the nucleus with increased blood pressure. Further research is needed to understand how the sentinel role of STAT3 in both endothelial cells and cardiomyocytes is integrated in order to coordinate the response of the heart to both physiological and pathological demands

Editorial: Methods and application in cardiovascular and smooth muscle pharmacology: 2021

Despite significant advances in basic, translational, and clinical research tackling heart disease, cardiovascular pathologies remain among the leading causes of mortality and morbidity worldwide, being responsible for one-third of global deaths as estimated by the WHO (Organization, 2021). The complexity of risk factors and pathways underlying the development of cardiovascular disorders (CVDs) limits the efficacy of a given therapeutic intervention and necessitates combined pharmacological approaches, as well as lifestyle modification to provide a reasonable health impact (Arnett et al., 2019). Be that as it may, there remains a considerable room for scientific inquiry in pursuit of novel and more refined avenues to prevent, diagnose, mitigate, and reverse different forms of cardiovascular ailment, as well as optimize patient management. Indeed, such a need for research in this field was even further emphasized as the world faced heightened health challenges during the COVID-19 pandemic with cardiovascular complications being among the most serious consequences of SARS-CoV-2 infection (Wehbe et al., 2020)

Advances in Cardiovascular Biomarker Discovery.

Cardiovascular diseases are the leading causes of mortality worldwide. Among them, hypertension and its pathological complications pose a major risk for the development of other cardiovascular diseases, including heart failure and stroke. Identifying novel and early stage biomarkers of hypertension and other cardiovascular diseases is of paramount importance in predicting and preventing the major morbidity and mortality associated with these diseases. Biomarkers of such diseases or predisposition to their development are identified by changes in a specific indicator's expression between healthy individuals and patients. These include changes in protein and microRNA (miRNA) levels. Protein profiling using mass spectrometry and miRNA screening utilizing microarray and sequencing have facilitated the discovery of proteins and miRNA as biomarker candidates. In this review, we summarized some of the different, promising early stage protein and miRNA biomarker candidates as well as the currently used biomarkers for hypertension and other cardiovascular diseases. Although a number of promising markers have been identified, it is unlikely that a single biomarker will unambiguously aid in the classification of these diseases. A multi-marker panel-strategy appears useful and promising for classifying and refining risk stratification among patients with cardiovascular disease.This research was funded by Qatar University [Grant QUERG-CMED-2020-3]

Acute exposure to cigarette smoking followed by myocardial infarction aggravates renal damage in an in vivo mouse model

Cigarette smoking (S) is a risk factor for progressive chronic kidney disease, renal dysfunction, and renal failure. In this study, the effect of smoking on kidney function was investigated in a mouse model of myocardial infarction (MI) using 4 groups: control (C), smoking (S), MI, and S+MI. Histological analysis of S+MI group showed alterations in kidney structure including swelling of the proximal convoluted tubules (PCTs), thinning of the epithelial lining, focal loss of the brush border of PCTs, and patchy glomerular retraction. Molecular analysis revealed that nephrin expression was significantly reduced in the S+MI group, whereas sodium-hydrogen exchanger-1 (NHE-1) was significantly increased, suggesting altered glomerular filtration and kidney functions. Moreover, S+MI group, but not S alone, showed a significant increase in the expression of connective tissue growth factor (CTGF) and fibrotic proteins fibronectin (FN) and α-smooth muscle actin (SMA), in comparison to controls, in addition to a significant increase in mRNA levels of IL-6 and TNF-α inflammatory markers. Finally, reactive oxygen species (ROS) production was significantly accentuated in S+MI group concomitant with a significant increase in NOX-4 protein levels. In conclusion, smoking aggravates murine acute renal damage caused by MI at the structural and molecular levels by exacerbating renal dysfunction.This work was supported by grants from the Medical Practice Plan (MPP) at AUB (grant title "Effect of Second Hand Smoking (SHS) on Cardiac and Vascular Smooth Muscle Remodeling: A Targeted and Global Approach." Lead PI: Firas Kobeissy, co-PIs: Asad Zeidan and Ahmad Husari), from Lebanese National Council for Scientific Research (Kazem Zibara), from AUB URB (Firas Kobeissy), and from Lebanese University grant (Kazem Zibara).Scopu

STAT3 and Endothelial Cell-Cardiomyocyte Dialog in Cardiac Remodeling

This article presents an overview of the central role of STAT3 in the crosstalk between endothelial cells and cardiac myocytes in the heart. Endothelial cell STAT3 has a key role in inflammation that underlies cardiovascular disease and impacts on cardiac structure and function. STAT3 in endothelial cells contributes to adverse cardiomyocyte genetic reprograming, for instance, during peripartum cardiomyopathy. Conversely, cardiomyocyte STAT3 is important for maintaining endothelial cell function and capillary integrity with aging and hypertension. In addition, STAT3 serves as a sentinel for stress in the heart. Recent evidence has revealed that the redox nature of STAT3 is regulated, and STAT3 is responsive to oxidative stress (ischemia-reperfusion) so as to induce protective genes. At the level of the mitochondrion, STAT3 is important in regulating reactive oxygen species (ROS) formation, metabolism, and mitochondrial integrity. STAT3 may also control calcium release from the ER so as to limit its subsequent uptake by mitochondria and the induction of cell death. Under normal conditions, some STAT3 localizes to intercalated discs of cardiomyocytes and serves to transmit pro-fibrotic gene induction signals in the nucleus with increased blood pressure. Further research is needed to understand how the sentinel role of STAT3 in both endothelial cells and cardiomyocytes is integrated in order to coordinate the response of the heart to both physiological and pathological demands

An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology

In its classical view, the renin angiotensin system (RAS) was defined as an endocrine system involved in blood pressure regulation and body electrolyte balance. However, the emerging concept of tissue RAS, along with the discovery of new RAS components, increased the physiological and clinical relevance of the system. Indeed, RAS has been shown to be expressed in various tissues where alterations in its expression were shown to be involved in multiple diseases including atherosclerosis, cardiac hypertrophy, type 2 diabetes (T2D) and renal fibrosis. In this chapter, we describe the new components of RAS, their tissue-specific expression, and their alterations under pathological conditions, which will help achieve more tissue- and condition-specific treatments

Distorted assessment of left atrial size by echocardiography in patients with increased aortic root diameter

Background: Left atrial (LA) size is frequently assessed by posterior-anterior linear measurement of LA (LAD P-A) in the parasternal long axis to expedite examination. Aging, changes in body surface area, and several cardiovascular pathologies can affect aortic root (AoR) size, thereby affecting LA anatomical shape. We hypothesized that AoR dilatation influences LAD P-A and consequently correct assessment of LA size. Results: We tested our hypothesis in a study of 70 patients with AoR diameter ranging from 2.7 to 4.8 cm. LA size assessed in parasternal long axis view as LAD P-A was compared to that with LA width and length acquired in the apical two and four chamber view. Simpson's method of discs was used as standard measurement to assess LA volume. We observed that LAD P-A in the parasternal long axis decreases when AoR diameter increases. Thus, the increase in LA size assessed in parasternal long axis did not correlate with the increase of LA volume. Further analysis revealed that a significant positive correlation was observed when LAV was plotted as a function of LAD P-A only for those with a normal size AoR. In contrast, LA volume increase correlated with LA diameters assessed in the apical two and four chamber view regardless of AoR size. Conclusions: Our study documents that increases in AoR impact on the linear measurement of LA, resulting in an underestimated LAD P-A. LA size ought to be calculated from the apical two and four chambers view parameters, especially in patients with AoR dilatation