Cardiac Mesenchymal Stem Cells Promote Fibrosis and Remodeling in Heart Failure

Hamid, Tariq; Xu, Yuanyuan; Ismahil, Mohamed Ameen; Rokosh, Gregg; Jinno, Miki; Zhou, Guihua; Wang, Qiongxin; Prabhu, Sumanth D.

doi:10.1016/j.jacbts.2022.01.004

“…Furthermore, in ischaemic stroke models, imatinib reduced cerebrovascular leakage and infarct size [ 39 , 56 ], but also haemorrhagic complications associated with the use of thrombolytic agents [ 56 ]. Interestingly, a recently published study in mice with permanent LAD ligation and subsequent heart failure showed that imatinib (30 mg/kg intraperitoneally for 3 weeks daily) alleviated long-term cardiac remodelling, inflammation and fibrosis [ 18 ], showing that low-dose imatinib can have beneficial effects in ischaemic injury without reperfusion. In line with these studies, the present study shows that imatinib is also able to reduce myocardial IR injury.…”

Section: Discussionmentioning

confidence: 99%

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction

Konijnenberg

¹

,

Luiken²,

Veltien

³

et al. 2023

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Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.

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“…Ventricular remodeling is a compensatory response to increased cardiac load and an important pathophysiological process in the early stage of heart failure [ 22 , 23 ]. Myocardial hypertrophy due to increased stress load is an important adaptive and compensatory response of cardiomyocytes to increased ventricular wall stress [ 24 , 25 ], allowing the heart to maintain the body's need for cardiac output for a period of time without clinical symptoms of heart failure. However, ventricular remodeling induced by prolonged pressure overload is one of the independent risk factors for the deterioration of cardiac function and cardiac death [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

A Heart Failure Model Established by Pressure Overload Caused by Abdominal Aortic Contraction in Rat

Dai

¹

,

Chen

²

,

Lin

³

et al. 2022

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Heart failure is a complex clinical syndrome in which ventricular filling or ejection capacity is impaired due to structural or functional diseases of the heart. In order to establish a stable heart failure model, we investigated cardiac parameters in rats with abdominal aortic contraction and normal rats, including the left ventricular posterior wall diameter (LVPWd), the interventricular septum thickness of end-diastolic (IVSd), the left ventricular end-diastolic diameter (LVEDd), the left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS). Rats were randomly divided into experimental group ( n = 20 ) and control group ( n = 20 ). The experimental group underwent modified abdominal aortic constriction, while the control group only isolated the abdominal aorta without constriction. The results showed that the survival rate of rats in the experimental group was 85% after one week of operation, while the survival rate of rats in the control group was 100%. Five weeks after operation, the left ventricular posterior wall diameter (LVPWd) and the interventricular septum thickness of end-diastolic (IVSd) in the experimental group were all increased compared with those in the control group, and the differences were statistically significant ( p < 0.05 ); the left ventricular end-diastolic diameter (LVEDd) in the experimental group showed an increasing trend compared with the control group, but p > 0.05 ; compared with the control group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the experimental group showed downward trend, but p > 0.05 . 10 weeks after operation, the LVPWd, IVSd, and LVEDd of the experimental group were increased compared with the control group, p < 0.05 , and the LVEF and LVFS of the experimental group were decreased compared with the control group, p < 0.05 . Compared with the control group, the BNP of the experimental group increased significantly, p < 0.05 . The heart weight index and left ventricular weight index of rats in the experimental group were significantly higher than those in the control group, p < 0.05 . HE staining showed that the myocardial cells in the experimental group increased in volume, disordered cell arrangement, widened gaps, increased nuclear hyperchromia, and uneven staining. This paper provides a theoretical basis for the study of heart failure.

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“…The TGF-β and WNT signaling pathways, which act as pro-fibrotic mediators in fibrosis formation, are activated in myofibroblasts [ 20 ]. Platelet-derived growth factor is also involved in the activation of fibroblasts via the regulation of matrix deposition, pericyte recruitment, and vascular migration [ 44 ]. The two critical fibrotic mediators are TGF-β and angiotensin.…”

Section: Molecular Mechanisms Of Cardiac Fibrosismentioning

confidence: 99%

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction

Raziyeva

¹

,

Kim

²

,

Zharkinbekov

³

et al. 2022

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Cardiac fibrosis is a common pathological consequence of most myocardial diseases. It is associated with the excessive accumulation of extracellular matrix proteins as well as fibroblast differentiation into myofibroblasts in the cardiac interstitium. This structural remodeling often results in myocardial dysfunctions such as arrhythmias and impaired systolic function in patients with heart conditions, ultimately leading to heart failure and death. An understanding of the precise mechanisms of cardiac fibrosis is still limited due to the numerous signaling pathways, cells, and mediators involved in the process. This review article will focus on the pathophysiological processes associated with the development of cardiac fibrosis. In addition, it will summarize the novel strategies for anti-fibrotic therapies such as epigenetic modifications, miRNAs, and CRISPR technologies as well as various medications in cellular and animal models.

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Cardiac Mesenchymal Stem Cells Promote Fibrosis and Remodeling in Heart Failure

Cited by 18 publications

References 64 publications

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction

A Heart Failure Model Established by Pressure Overload Caused by Abdominal Aortic Contraction in Rat

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction

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