Diagnosis of cardiac allograft rejection by the detection of circulating plasma cardiac myosin light chains

Kawauchi, M; Yazaki, Yoshio; Oka, Teruaki; Okabe, Hideo; Mathison, Megumi; Nakajima, Jun; Morizuki, Osamu; Kawaguchi, Go; Koseni, K; Takeda, Makoto; Chikada, Masahide; Furuse, Akira

doi:10.1007/bf02470771

Cited by 10 publications

(4 citation statements)

References 6 publications

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“…In murine and nonhuman primate models, alterations in the expression of several actins and myosins have been observed in the context of cardiac rejection. [31][32][33][34] In addition, an increase in the levels of anti-actin and anti-myosin antibodies has been observed in EMB and serum from rejection patients. [35][36][37][38] These results highlight the key role of these molecules in the pathophysiology of cardiac rejection.…”

Section: Discussionmentioning

confidence: 99%

Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients

et al. 2023

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Background. Given the central role of sarcomeric dysfunction in cardiomyocyte biology and sarcomere alterations described in endomyocardial biopsies of transplant patients with rejection, we hypothesized that the serum expression levels of genes encoding sarcomeric proteins were altered in acute cellular rejection (ACR). The aim of this study is to identify altered sarcomere-related molecules in serum and to evaluate their diagnostic accuracy for detecting rejection episodes. Methods. Serum samples from transplant recipients undergoing routine endomyocardial biopsies were included in an RNA sequencing analysis (n = 40). Protein concentrations of alpha-cardiac actin were determined using a specific enzyme-linked immunoassay (n = 80). Results. We identified 17 sarcomeric genes differentially expressed in patients with clinically relevant rejection (grade ≥2R ACR). A receiver operating characteristic curve was done to assess their accuracy for ACR detection and found that 6 relevant actins, myosins, and other sarcomere-related genes showed great diagnostic capacity with an area under the curve (AUC) > 0.800. Specifically, the gene encoding alpha-cardiac actin (ACTC1) showed the best results (AUC = 1.000, P < 0.0001). We determine ACTC1 protein levels in a larger patient cohort, corroborating its overexpression and obtaining a significant diagnostic capacity for clinically relevant rejection (AUC = 0.702, P < 0.05). Conclusions. Sarcomeric alterations are reflected in peripheral blood of patients with allograft rejection. Because of their precision to detect ACR, we propose sarcomere ACTC1 serum expression levels as potential candidate for to be included in the development of molecular panel testing for noninvasive ACR detection.

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Section: Discussionmentioning

confidence: 99%

Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients

et al. 2023

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“…11,12 FITC-labeled decoy was injected to confirm the transfection. E2F decoy (nϭ5) or mismatch decoy (nϭ5) was transfected into the allografts; control donor hearts did not receive any gene transfection (nϭ4).…”

Section: Methodsmentioning

confidence: 99%

“…11 Transfection of FITC decoy resulted in widespread distribution of fluorescence in medial vascular SMCs and …”

Section: Localization and Kinetics Of Fitc-labeled Phosphorothioate Odnmentioning

confidence: 99%

Gene Therapy for Attenuating Cardiac Allograft Arteriopathy Using Ex Vivo E2F Decoy Transfection by HVJ-AVE–Liposome Method in Mice and Nonhuman Primates

Kawauchi¹,

Suzuki²,

Morishita³

et al. 2000

Circulation Research

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Abstract-Cardiac allograft arteriopathy, which limits the long-term survival of recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. The transcription factor E2F plays a pivotal role in the coordinated transcription of cell-cycle regulatory genes. To test the hypothesis that double-stranded DNA with specific affinity for E2F (E2F decoy) is effective in preventing intimal hyperplasia, we performed ex vivo single intraluminal delivery of E2F decoy into cardiac allografts of mice and Japanese monkeys using the hemagglutinating virus of Japan (HVJ) artificial viral envelope-liposome method. In murine models, antisense cyclin-dependent kinase 2 (cdk2) kinase oligodeoxynucleotide (ODN) and no transfers were performed to compare the effects. Severe intimal thickening was observed, and multiple cell-cycle regulatory genes were enhanced in untreated allografts. E2F decoy prevented neointimal formation and suppressed these genes for up to 8 weeks, whereas antisense cdk2 kinase ODN had limited effects. In primate models, E2F decoy dramatically prevented neointimal thickening and suppressed multiple cell-cycle regulatory genes, whereas intimal thickening developed in the nontransfected or mismatch decoy-transfected allografts. Gel mobility shift assay proved the specific effects of E2F decoy, and reverse transcriptase-polymerase chain reaction documented that neither complication nor dissemination of HVJ into other organs was observed. We demonstrate that ex vivo gene delivery to allografts is a potent strategy to modify allograft gene expression, resulting in prevention of graft arteriopathy without systemic adverse effects. Key Words: primate Ⅲ heart transplantation Ⅲ transcription factor Ⅲ arteriosclerosis Ⅲ gene therapy C ardiac transplantation often results in accelerated graft coronary disease in long-term survivors. 1 Neointimal hyperplasia of the coronary arteries results from vascular smooth muscle cell (SMC) proliferation; this proliferation is dependent on the coordinated actions of cell-cycle regulatory genes. 2 Recently, we reported that antisense cyclin-dependent kinase (cdk) 2 kinase oligodeoxynucleotide (ODN) prevents neointimal formation in murine cardiac allografts. 3 The transcription factor E2F regulates multiple cell-cycle regulatory genes, which are critical to the process of cell growth and proliferation. 4,5 Double-stranded DNA with high affinity for E2F acting as a decoy (E2F decoy) inhibits cell-cycle regulatory gene expression and SMC proliferation in rat carotid injury models. 6 However, the effect of E2F decoy in preventing graft coronary arterial neointimal formation has not been investigated. Several gene therapy trials have been performed in search of methods to prevent and treat several diseases using the hemagglutinating virus of Japan (HVJ)-liposome method. 7 Recently, HVJ artificial viral envelope (AVE) liposome, which is a modified method of HVJliposome delivery, has been demonstrated to increase efficiency of cellular uptake of ODN. 8...

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“…Pathogenesis of these cardiac rejections remains unclear. As an experimental model of graft rejection, heterotopic transplantation of cardiac allografts has been developed in Japanese monkeys [17]. These models are useful for studies of the pathophysiology of rejection; the histological findings are similar to the acute and chronic rejection seen in clinical heart transplantation.…”

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confidence: 99%

Altered expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in acutely rejected myocardium and coronary arteriosclerosis in cardiac allografts of nonhuman primates

Suzuki¹,

Isobe²,

Kawauchi³

et al. 2000

Transplant Int

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Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are important in any process of tissue remodeling. However, there is no report evaluating their expression in cardiac allografts in human or non-human primates. Heterotopic cardiac transplantation was performed on Japanese monkeys. Subjects were treated with chimeric anti-human lymphocyte function-associated antigen-1 monoclonal antibody for 2 weeks. Heart grafts were harvested at days 1-95 (n = 7). Native monkey hearts were used as controls (n = 2). We examined expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 using immunohistochemistry and in situ reverse transcriptase polymerase chain reaction (RT-PCR). In the myocardium, the expression of MMP-2 was increased in the spindle-shaped cells of acutely rejected myocardial interstitium and prior to the presence of mononuclear cell infiltration at days 1-41. TIMP-1 and 2 expression was enhanced in association with the progression of fibrosis at days 40-95. In the coronary arteries of chronically rejected allografts, enhanced MMP and decreased TIMP expression was observed in both thickened intima and media at days 40-95. The medial MMP mRNA expression was observed before the development of intimal thickening occurred at days 7-28. MMPs are critical for the progression of acute and chronic rejection, and TIMP predominance plays important roles in fibrosis in association with acute rejection. Expression of MMPs and TIMPs is a sensitive indicator of acute and chronic cardiac rejection.

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Diagnosis of cardiac allograft rejection by the detection of circulating plasma cardiac myosin light chains

Cited by 10 publications

References 6 publications

Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients

Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients

Gene Therapy for Attenuating Cardiac Allograft Arteriopathy Using Ex Vivo E2F Decoy Transfection by HVJ-AVE–Liposome Method in Mice and Nonhuman Primates

Altered expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in acutely rejected myocardium and coronary arteriosclerosis in cardiac allografts of nonhuman primates

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