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Nonmuscle and smooth muscle myosin heavy chain expression in rejected cardiac allografts. A study in rat and monkey
1Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Insights
Altered myosin heavy chain (MHC) isoform expression, specifically SMemb and SM2, indicates acute and chronic cardiac rejection. This finding aids in diagnosing cardiac transplant rejection.
Area of Science:
- Cardiovascular Biology
- Transplantation Immunology
- Molecular Pathology
Background:
- Accurate diagnosis of acute and chronic cardiac rejection is crucial for transplant success but remains challenging.
- Vascular myosin heavy chain (MHC) isoforms (SM1, SM2, SMemb) include SM2 in differentiated smooth muscle cells (SMCs) and SMemb in fetal aorta SMCs.
Purpose of the Study:
- To assess the utility of myosin heavy chain (MHC) isoform expression for diagnosing acute and chronic cardiac rejection.
- To analyze changes in MHC expression during cardiac allograft rejection.
Main Methods:
- Heterotopic cardiac transplantation in rats and monkeys.
- Immunohistochemistry, electron microscopy, and Northern blot assays to evaluate MHC expression patterns.
Main Results:
- SMemb expression was detected in spindle-shaped cells within acutely rejected myocardium, identified as activated fibroblasts/myofibroblasts.
- SMemb mRNA levels increased with acute rejection progression.
- Chronically rejected allografts showed increased SMemb and decreased SM2 in thickened intima and media, with reduced SM2 preceding intimal thickening, indicating modulated SMCs.
Conclusions:
- Changes in myosin heavy chain (MHC) isoform expression serve as a sensitive diagnostic marker for acute and chronic cardiac rejection.
- Further research into the pathophysiology of altered MHC isoform expression is needed to understand cardiac rejection pathogenesis.
Background:
Diagnosis of acute rejection and graft arteriosclerosis (chronic rejection) is critical to the success of cardiac transplantation, but accurate diagnosis is often difficult. We have reported that there are three types of vascular myosin heavy chain (MHC) isoforms: SM1, SM2, and SMemb. SM2 is specifically expressed in differentiated smooth muscle cells (SMCs). SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of fetal aorta.
Methods And Results:
To evaluate the usefulness of MHC expression for diagnosis and analysis of acute and chronic rejection, heterotopic cardiac transplantation was performed in rats and monkeys. Immunohistochemistry, electron microscopy, and Northern blot assay were performed to evaluate MHC expression. SMemb was expressed in spindle-shaped cells located in acutely rejected myocardium in the rats and monkeys. These cells were also observed in areas lacking cellular infiltration. These SMemb-positive cells were activated fibroblasts or myofibroblasts. SMemb mRNA was enhanced parallel to the progression of acute rejection. In the coronary arteries of chronically rejected allografts, enhanced SMemb and reduced SM2 expression was observed in both thickened intima and media. The reduced medial SM2 expression was observed before the intimal thickening occurred. These cells were phenotypically modulated SMCs.
Conclusions:
Altered expression of MHC isoforms is a sensitive indicator in the diagnosis of acute and chronic cardiac rejection. The pathophysiology of this alteration in MHC isoform expression should be studied further to elucidate the pathogenesis of cardiac rejection.