α1A Adrenoreceptor blockade attenuates myocardial infarction by modulating the integrin-linked kinase/TGF-β/Smad signaling pathways

Alrasheed et al. BMC Cardiovascular Disorders https://doi.org/10.1186/s12872-023-03188-w (2023) 23:153 BMC Cardiovascular Disorders Open Access RESEARCH α1A Adrenoreceptor blockade attenuates myocardial infarction by modulating the integrin‑linked kinase/TGF‑β/Smad signaling pathways Nawal M. Alrasheed1, Raghad B. Alammari2, Tahani K. Alshammari1, Maha A. Alamin1* , Abeer O. Alharbi1, Asma S. Alonazi1, Anfal F. Bin Dayel1 and Nouf M. Alrasheed1 Abstract Background Myocardial infarction (MI) is considered a public health problem. According to the World Health Organization, MI is a leading cause of death and comorbidities worldwide. Activation of the α1A adrenergic receptor is a contributing factor to the development of MI. Tamsulosin, an α1A adrenergic blocker, has gained wide popularity as a medication for the treatment of benign prostatic hyperplasia. Limited evidence from previous studies has revealed the potential cardioprotective effects of tamsulosin, as its inhibitory effect on the α1A adrenoceptor protects the heart by acting on the smooth muscle of blood vessels, which results in hypotension; however, its effect on the infarcted heart is still unclear. The mechanisms of the expected cardioprotective effects mediated by tamsulosin are not yet understood. Transforming growth factor-beta (TGF-β), a mediator of fibrosis, is considered an attractive therapeutic target for remodeling after MI. The role of α1A adrenoceptor inhibition or its relationships with integrin-linked kinase (ILK) and TGF-β/small mothers against decapentaplegic (Smad) signaling pathways in attenuating MI are unclear. The present study was designed to investigate whether tamsulosin attenuates MI by modulating an ILK-related TGF-β/ Smad pathway. Methods Twenty-four adult male Wistar rats were randomly divided into 4 groups: control, ISO, TAM, and ISO + TAM. ISO (150 mg/kg, intraperitoneally) was injected on Days 20 and 21 to induce MI. Tamsulosin (0.8 mg/kg, orally) was administered for 21 days, prior to ISO injection for 2 consecutive days. Heart-to-body weight ratios and cardiac and fibrotic biomarker levels were subsequently determined. ILK, TGF-β1, p-Smad2/3, and collagen III protein expression levels were determined using biomolecular methods. Results Tamsulosin significantly attenuated the relative heart-to-body weight index (p < 0.5) and creatine kinase-MB level (p < 0.01) compared with those in the ISO control group. While ISO resulted in superoxide anion production and enhanced oxidative damage, tamsulosin significantly prevented this damage through antioxidant defense mechanisms, increasing glutathione and superoxide dismutase levels (p < 0.05) and decreasing lipid peroxide oxidation levels (p < 0.01). The present data revealed that tamsulosin reduced TGF-β/p-Smad2/3 expression and enhanced ILK expression. *Correspondence: Maha A. Alamin Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Alrasheed et al. BMC Cardiovascular Disorders (2023) 23:153 Page 2 of 14 Conclusion Tamsulosin may exert a cardioprotective effect by modulating the ILK-related TGF-β/Smad signaling pathway. Thus, tamsulosin may be a useful therapeutic approach for preventing MI. Keywords Tamsulosin, Myocardial infarction, Integrin-linked kinase, Fibrosis, Isoproterenol Introduction Myocardial infarction (MI) is a leading cause of cardiovascular morbidity and mortality despite the control of risk factors, such as arteriosclerosis [1–4]. Since coronary diseases are the leading cause of death, the need for biomedical research to advance medical treatments for cardiovascular diseases is urgent [5]. Currently, cardiovascular-focused research has advanced the understanding of the underlying molecular processes and cell‒cell interactions that coordinate myocardial growth and fibrosis [6]. Myocardial fibrosis is controlled by numerous processes of fibrotic growth involving transforming growth factors (TGFs) [7–12]. Evidence indicates that increased expression of the downstream effectors of TGF-β signaling is associated with infarct healing. Although evidence also suggests that bioactive TGF-β is secreted in the cardiac extracellular matrix after infarction reperfusion, the mechanisms of TGF-β activation in the infarcted heart are poorly understood [13–15]. TGF-βs activate small mothers against decapentaplegic2/3 (Smad2/3) cascades and possibly activate Smad1 and Smad5 in certain cell types, providing an alternative Smad-dependent pathway for signal transduction [16, 17]. Taking into consideration the wide range of effects of Smad3 on all cell types, it is unclear whether the improved remodeling exhibited by mice with loss of Smad3 results from fibroblast-mediated actions. Therefore, it is crucial to investigate the role of Smad-dependent signaling in MI. In addition, previous studies have reported that matrix attachment is necessary for activation by growth factors, including TGF-β [17]. The process of fibrosis is also induced by the collaboration of TGF in addition to its receptors and extracellular matrix (ECM) receptors, such as integrins [11]. Integrins are transmembrane receptors that attach cells to the matrix and mediate outside-in signaling and insideout signaling, controlling the activities of growth factor receptors, cytoplasmic kinases and ion channels [12]. The serine/threonine integrin-linked kinase (ILK) exerts a notable role in the integrin-actin interaction in addition to its structural and signaling roles in the function of integrins. Published reports indicate that ILK gene therapy dramatically improves cardiac function and attenuates ventricular remodeling in rat models of myocardial infarction, but it remains unknown whether, in the absence of underlying cardiac ischemia, ILK gene therapy improves cardiac performance in heart failure models [18]. Interestingly, recent data also demonstrate that α1A adrenocep (...truncated)