The Effect of Calcineurin Inhibitors on MMPs Activity in Heart and Their Side Effects—A Review of Literature

Abstract

This review focuses on the role of metalloproteinases in the pathogenesis of myocardial injury in various disease entities. It reveals how the expression and serum levels of metalloproteinases and their inhibitors change in many disease states. At the same time, the study offers a review of the impact of immunosuppressive treatment on this relationship. Modern immunosuppressive treatment is based mainly on the use of calcineurin inhibitors, including cyclosporine A and tacrolimus. The use of these drugs may carry a number of side effects, specifically to the cardiovascular system. The scale and degree of long-term influence on the organism remains unclear, but a significant risk of complications for transplant recipients who take immunosuppressive drugs as part of their daily treatment is to be expected. Therefore, the knowledge on this subject should be expanded and the negative effects of post-transplant therapy minimized. Immunosuppressive therapy plays an important role in the expression and activation of tissue metalloproteinases and their specific inhibitors, which leads to many tissue changes. The presented study is a collection of research results on the effects of calcineurin inhibitors on the heart, with particular emphasis placed on the participation of MMP-2 and MMP-9. It is also an analysis of the effects of specific heart diseases on myocardial remodeling through inductive or inhibitory effects on matrix metalloproteinases and their inhibitors.

The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart

“…The most frequently cited cause of hypertension in organ recipients is chronic cyclosporin treatment. Clinically, the use of CsA is associated with a significantly higher risk of fibrosis and myocardial remodeling than TAC [7,17,43]. This phenomenon can also be seen in the results presented above.…”

“…Immunosuppressive drugs may affect the MMP/TIMP imbalance in the heart, leading to connective tissue accumulation and myocardial fibrosis, degenerative changes in muscle fibers, and pathological tissue remodeling [7,38]. Currently, there is a lack of studies in the literature indicating the effects of commonly used triple-drug immunosuppressive treatment regimens on morphological changes in the heart and the activities of MMP-2, MMP-9, TIMP-1, and TIMP-2.…”

“…This protocol results in one-year graft survival in 90% of cases and avoids episodes of acute organ rejection in 80% of cases. Alternative treatment regimens allow the use of an mTOR inhibitor, including rapamycin, as an alternative to CNI or MMF [3][4][5][6][7].…”

“…These drugs can affect tissue remodeling by disrupting the balance between metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). This leads to the remodeling of the extracellular matrix (ECM), cell hypertrophy, accumulation of collagen fibers, and ultimately limits the normal function of the entire organ [7,18].…”

Immunosuppressive Agents—Effects on the Cardiovascular System and Selected Metabolic Aspects: A Review

“…CsA has many proven cardiovascular side effects, alongside its impact on myocardial remodeling [33]. In rats receiving CsA at a dose of 15 mg/kg for 21 days, the myocardium underwent remodeling.…”