Procollagen C-Proteinase Enhancer 1 (PCPE-1) is a marker of myocardial fibrosis and impaired cardiac function in a murine model of pressure overload

Abstract

Aims: Procollagen C-proteinase enhancer 1 (PCPE-1) is an extracellular matrix protein and a major regulator of fibrillar collagen biosynthesis. Previous work has shown that its abundance is often increased in the context of tissue repair and fibrosis. The present study was designed to evaluate its potential as a biomarker of myocardial interstitial fibrosis (MIF), a well-established pathogenic pathway leading to heart failure. Methods and Results: Cardiac fibrosis was induced in rats using an optimized model of chronic pressure overload triggered by angiotensin II and Nω-nitro-L-arginine methyl ester (L-NAME). All treated animals suffered from heart hypertrophy and the increase in heart collagen volume fraction (CVF), evidenced by histology and 68Ga-Collagelin uptake, confirmed the development of cardiac fibrosis. Functional analysis by simultaneous PET-MRI further showed that our model closely reflected the pathological features seen in human MIF, including left ventricle thickening and diastolic dysfunction associated with decreased ejection fraction. PCPE-1 mRNA and protein levels were augmented by factors of 3.4 and 6.1 respectively in the heart tissue of treated rats. Moreover, protein abundance was well-correlated with CVF (r=0.92, p<0.0001) and PCPE-1 immuno-detection mainly localized the protein to fibrotic areas. Finally, PCPE-1 plasma levels measured by ELISA were increased in fibrotic rats compared to controls. Conclusion: Together, our findings demonstrate that PCPE-1 levels in the heart and circulation tightly reflect the cardiac fibrosis status and heart function impairment in rats and suggest that it could be a very useful marker to monitor human heart diseases leading to fibrosis.

Procollagen C-proteinase enhancer-1 (PCPE-1), a potential biomarker and therapeutic target for fibrosis

“…In the fibrotic diaphragms of the mdx mice collected at 4 and 8.5 months of age, there was an overall increase in PCPE-1, detected by immunoblotting and immunofluorescence, which was not quantified but seemed to follow the marked increase in collagen I [125] . Notably and similarly to the observations made in models of cardiac and liver fibrosis [100] , [113] , [125] , PCPE-1 and collagen I were also co-localized in diaphragm tissue. Finally, this study showed that the elevation of PCPE-1 levels in mdx mouse plasma was comparable to that observed for the N-propeptide of collagen III (PIIINP), an established marker of fibrosis [145] .…”

“…It was also co-localized with fibrotic areas in the myocardium. Notably, both in this study and in the model of MI described above, there was an excellent correlation between the PCPE-1 protein quantified in the heart by immunoblotting and the amount of collagen I measured through immunoblotting or Sirius Red staining (r = 0.82 and 0.92) [100] , [113] .…”

“…It can be induced in animal models by a continuous subcutaneous infusion of angiotensin II, a potent vasoconstrictor and upstream regulator of aldosterone production. After the first reports showing that PCPE-1 is more abundant in mouse heart after angiotensin II treatment [111] , [112] , the relationship between angiotensin II, cardiac fibrosis and PCPE-1 induction was recently confirmed in a more extensive study combining the effect of angiotensin II with a NO synthase inhibitor in rats [113] . In this model, PCPE-1 protein was increased 6-fold at the heart tissue level and to a lesser extent in the circulation.…”

“…What is presently well established is that PCPE-1 is found in human serum and plasma and can be easily detected and quantified using several techniques such as immunoblotting, ELISA and mass spectrometry [66] , [113] , [129] , [131] , [156] . According to present literature and public databases, PCPE-1 is also found in cerebrospinal fluid [157] , [158] , [159] , [160] but almost undetectable in saliva, urine or broncho-alveolar fluid.…”

“…According to present literature and public databases, PCPE-1 is also found in cerebrospinal fluid [157] , [158] , [159] , [160] but almost undetectable in saliva, urine or broncho-alveolar fluid. Even though the most comprehensive studies establishing the relationship between the severity of tissue fibrosis and circulating levels of PCPE-1 were performed in murine models [113] , [125] , [126] , measuring PCPE-1 in human plasma has also revealed elevated concentrations in diseased individuals with a strong suspicion of liver or kidney fibrosis [129] , [131] . Moreover, there are some good hints that PCPE-1 monitoring allows the early detection of fibrogenic/pre-fibrotic stages and is closely correlated with fibrosis severity [125] , [126] , [136] .…”