Bader Eddin Lujain, Nagoor Meeran Mohamed Fizur, Kumar Jha Niraj, Goyal Samer N, Ojha Shreesh
Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, India.
Animal Model Exp Med. 2025 Jan;8(1):67-91. doi: 10.1002/ame2.12496. Epub 2024 Dec 17.
Cardiac injury initiates repair mechanisms and results in cardiac remodeling and fibrosis, which appears to be a leading cause of cardiovascular diseases. Cardiac fibrosis is characterized by the accumulation of extracellular matrix proteins, mainly collagen in the cardiac interstitium. Many experimental studies have demonstrated that fibrotic injury in the heart is reversible; therefore, it is vital to understand different molecular mechanisms that are involved in the initiation, progression, and resolution of cardiac fibrosis to enable the development of antifibrotic agents. Of the many experimental models, one of the recent models that has gained renewed interest is isoproterenol (ISP)-induced cardiac fibrosis. ISP is a synthetic catecholamine, sympathomimetic, and nonselective β-adrenergic receptor agonist. The overstimulated and sustained activation of β-adrenergic receptors has been reported to induce biochemical and physiological alterations and ultimately result in cardiac remodeling. ISP has been used for decades to induce acute myocardial infarction. However, the use of low doses and chronic administration of ISP have been shown to induce cardiac fibrosis; this practice has increased in recent years. Intraperitoneal or subcutaneous ISP has been widely used in preclinical studies to induce cardiac remodeling manifested by fibrosis and hypertrophy. The induced oxidative stress with subsequent perturbations in cellular signaling cascades through triggering the release of free radicals is considered the initiating mechanism of myocardial fibrosis. ISP is consistently used to induce fibrosis in laboratory animals and in cardiomyocytes isolated from animals. In recent years, numerous phytochemicals and synthetic molecules have been evaluated in ISP-induced cardiac fibrosis. The present review exclusively provides a comprehensive summary of the pathological biochemical, histological, and molecular mechanisms of ISP in inducing cardiac fibrosis and hypertrophy. It also summarizes the application of this experimental model in the therapeutic evaluation of natural as well as synthetic compounds to demonstrate their potential in mitigating myocardial fibrosis and hypertrophy.
心脏损伤会启动修复机制，导致心脏重塑和纤维化，而这似乎是心血管疾病的主要原因。心脏纤维化的特征是细胞外基质蛋白的积累，主要是心脏间质中的胶原蛋白。许多实验研究表明，心脏的纤维化损伤是可逆的；因此，了解参与心脏纤维化起始、进展和消退的不同分子机制对于开发抗纤维化药物至关重要。在众多实验模型中，最近重新引起人们兴趣的模型之一是异丙肾上腺素（ISP）诱导的心脏纤维化。ISP是一种合成儿茶酚胺、拟交感神经药和非选择性β-肾上腺素能受体激动剂。据报道，β-肾上腺素能受体的过度刺激和持续激活会诱导生化和生理改变，并最终导致心脏重塑。几十年来，ISP一直被用于诱导急性心肌梗死。然而，低剂量和慢性给予ISP已被证明会诱导心脏纤维化；近年来这种做法有所增加。腹腔内或皮下注射ISP已广泛用于临床前研究，以诱导以纤维化和肥厚为特征的心脏重塑。通过触发自由基释放而诱导的氧化应激以及随后细胞信号级联的紊乱被认为是心肌纤维化的起始机制。ISP一直被用于在实验动物和从动物分离的心肌细胞中诱导纤维化。近年来，许多植物化学物质和合成分子已在ISP诱导的心脏纤维化中进行了评估。本综述专门全面总结了ISP诱导心脏纤维化和肥厚的病理生化、组织学和分子机制。它还总结了该实验模型在天然和合成化合物治疗评估中的应用，以证明它们在减轻心肌纤维化和肥厚方面的潜力。
