The Journal of Maternal-Fetal & Neonatal Medicine
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Calponin levels in term laboring women Yuri Perlitz, Moshe Ben-Ami, Aviva Peleg, Ido Izhaki & Izhar Ben-Shlomo To cite this article: Yuri Perlitz, Moshe Ben-Ami, Aviva Peleg, Ido Izhaki & Izhar Ben-Shlomo (2015) Calponin levels in term laboring women, The Journal of Maternal-Fetal & Neonatal Medicine, 28:10, 1158-1160, DOI: 10.3109/14767058.2014.947570 To link to this article: http://dx.doi.org/10.3109/14767058.2014.947570
Accepted author version posted online: 22 Jul 2014. Published online: 12 Aug 2014. Submit your article to this journal
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [Chinese University of Hong Kong]
Date: 05 November 2015, At: 22:50
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(10): 1158–1160 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.947570
ORIGINAL ARTICLE
Calponin levels in term laboring women Yuri Perlitz1,2, Moshe Ben-Ami1,2, Aviva Peleg3, Ido Izhaki4, and Izhar Ben-Shlomo1,2 1
Department of OB&GYN, The Baruch Padeh Medical Center, Poriya, Israel, 2Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel, Research Laboratory, The Baruch Padeh Medical Center, Poriya, Israel, and 4Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel
Downloaded by [Chinese University of Hong Kong] at 22:50 05 November 2015
3
Abstract
Keywords
Objective: Calponin, a specific smooth muscle contraction regulatory troponin-like protein, is present in large quantities in uterine smooth muscle. Serum troponin levels rise in acute myocardial infarction, and creatine phosphokinase levels rise at high physical activity, both due to destruction of cardiac and striated muscle fibers. We hypothesize that the active labor process may cause uterine smooth muscle cell damage, which may result in rising maternal serum calponin levels. This was a preliminary study, searching for a new biomarker for preterm labor. Methods: The study group included laboring term primiparous women with a singleton fetus. The control group included similar demographic and pregnancy characteristics pregnant women not in labor. Maternal serum levels of calponin basic isoform were measured evaluated and compared in both groups. Results: Study group included 100 pregnant women. Calponin serum levels were higher in the active labor (794 ± 974 ng/mL) than in the group not in labor (591 ± 587 ng/mL), although it did not reach statistical significance. Gender and neonatal weight were similar in the two study groups. Conclusions: Calponin serum levels showed moderate elevation during active labor, compared to the levels in a cohort of pregnant comparable women at the same gestational weeks but not in labor.
Calponin, labor, pregnancy, preterm labor
Introduction Preterm labor (PTL) continues to pose a major concern in modern obstetrical practice since prematurity complications are the leading cause of perinatal morbidity and mortality [1,2]. It is often difficult to distinguish between contractions leading to cervical change and preterm birth and those which do not. Women with PTL usually require hospitalization with specific attention and therapeutic measures. On the other hand, Braxton–Hicks contractions, an un-harmful physiological phenomenon, do not require intervention [3]. Both cervical fibronectin and cervical length have been evaluated in the diagnosis of PTL, but both have low positive predictive values [4]. An accurate and rapid test, which could distinguish between the types of uterine contractions, would aid in the prevention of PTL. Smooth muscle contractions are regulated primarily by the reversible phosphorylation of myosin light chain, which is triggered by an increase in sarcoplasmic-free Ca2+ concentration. However, contractions can be modulated by other signal transduction pathways, one of which involves the thin Address for correspondence: Yuri Perlitz, MD, Department of OB&GYN, The Baruch Padeh Medical Center, Poriya, MPO Lower Galilee, 15208, Tiberias, Israel. Tel: +972-6652309. E-mail: [email protected]
History Received 9 February 2014 Accepted 19 July 2014 Published online 12 August 2014
filament-associated calponin [5]. Calponin is a thin filament, actin regulatory protein, which has three isoforms, each a product of separate genes [6–8]. Calponin was originally identified as a protein that interacts with actin and directly inhibits actin-activated Mg-ATPase activity of myosin [9,13]. We hypothesized that calponin, a smooth muscle troponinlike protein, may serve as a biomarker for diagnosing true PTL. This was based on the following facts: (1) the h1 (basic) isoform of calponin is the most abundant and specific protein of smooth muscle [10]; (2) during second and third trimesters of pregnancy, the uterus is the organ containing the largest volume of smooth muscle and therefore, calponin; and (3) serum creatine phosphokinase (CPK) rises when overuse of striated muscles occurs [11], and serum troponin rises when cardiac ischemia occurs [12,13]. The process of contractions resulting in true labor may results in myometrial destruction rising maternal serum calponin levels. In a first step to determine whether calponin h1 can be used as a biomarker for labor, we examined whether serum levels increased during active labor in term deliveries.
Methods Primiparous low-risk women included in our study were at term (37–41 weeks gestation) with a singleton fetus with no
Calponin term laboring women
DOI: 10.3109/14767058.2014.947570
Table 1. Calponin levels and other characteristics.
Age (years) Gestational week Calponin (pg/ml) Cervical dilatation (cm) Birth weight (g)
Active labor N ¼ 50
No labor N ¼ 50
Mean ± SD (n)
Mean ± SD (n)
p
28.4 ± 5.2 39.6 ± 1.1 794.8 ± 974.9 6.0 ± 1.6 3364.9 ± 461.6
31.1 ± 5.1 39.6 ± 1.0 591.3 ± 587.6 0.4 ± 0.8 3430.1 ± 486.5
50.05 NS NS 50.001 NS
Downloaded by [Chinese University of Hong Kong] at 22:50 05 November 2015
All values are expressed as mean, standard deviation.
known anomaly. We recruited two groups. The study group included women in spontaneous active labor at term defined as cervical dilatation 4 cm and 3 contractions in 10 min with intact membranes, not receiving antibiotics, oxytocin or analgesia for pain. The control group included women with the same inclusion criteria but not in labor as defined as cervical dilatation 52 cm, 52 contractions in a 10-min period and no vaginal bleeding or ruptured membranes. All study participants were non-smokers and did not consume any medications other than iron and folic acid supplementation. The study was approved by our institutional review board, and all participants gave informed consent. Serum h1 calponin concentration was measured in duplicates using ELISA (Cusabio Biotech Co., Wuhan, China). The minimum detectable value of calponin was 40 pg/ml and the maximum was 24 000 pg/ml. Statistical analysis between the groups was by student t-test. A p50.05 was considered significant.
Results Fifty women in each group were recruited to the study. Calponin levels and other relevant characteristics are listed in Table 1. There was a significant difference in the age of the two study groups. As expected, cervical dilatation was statistically different between groups at the time of blood draw. Calponin levels were higher in the active labor group than in the no labor group, although this did not reach statistical significance.
Discussion We evaluated calponin, a smooth muscle contraction regulatory protein, as a possible biomarker for labor in term patients. If calponin levels were elevated in term laboring patients, we theorized it might be a possible marker of labor in preterm women. Our hypothesis theorized that calponin may be discharged from the contracting uterine smooth muscles into the maternal serum, as a result of uterine smooth muscle fibers destruction during active labor. Our assumption was based on the observation of CPK rising levels as a result of striated muscles destruction during strenuous physical activity [11]. Furthermore, rising serum troponin levels are well established after cardiac muscles destruction as a result of a coronary event [12,13]. Our results revealed no significant difference in calponin levels in the serum of women in active labor at term compared to women not in labor. In 1988, Takahashi et al. reported for the first time the presence of calponin in bovine aorta smooth muscles [14].
1159
This 35 000 molar ratio protein function was suggested to be an additional Ca2+ regulatory component of smooth muscle thin filament. Suzuki et al. evaluated calponin as a possible biomarker for aortic dissection (AD) [10]. They included in their study 59 cases of radiographically proven acute AD and 158 controls with an initial suspicion of AD but a different final diagnosis. Of the 59 AD cases, the basic calponin isoform showed more than threefold increase for all dissections when sampled within the first six hours of symptom onset. The authors of that study concluded that basic calponin assay may improve acute AD diagnosis. Cornwell et al. tested the hypothesis that the levels and subcellular distribution of caldesmon, calponin and cGMPdependent protein kinase are regulated with the hormonal milieu of human pregnancy. Their results demonstrated that although cGMP-dependent protein kinase was significantly reduced in the human uterus during pregnancy, caldesmon expression was significantly increased, and both caldesmon and calponin were redistributed to a readily extractable subcellular pool. These data suggest that cGMP-dependent protein kinase does not mediate gestational quiescence. Redistribution of thin filament-associated proteins, however, may alter uterine smooth muscle tone or the cytoskeletal framework of myocytes to maintain gestation despite the substantial distention that accompanies all intrauterine pregnancies [15]. This is the first study to measure calponin levels in a cohort of women at term in active labor. Although we were able to demonstrate a moderate elevation of calponin levels in the laboring group, the difference was not statistically different. It would seem that calponin is not a good marker of labor at term, although a study of women with PTL is needed to conclude if the same is true in preterm women with contractions.
References 1. Heron M, Sulton PD, Xu J. Annual summary of vital statistics: 2007. Pediatrics 2010;125:4–15. 2. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75–84. 3. Lockwood CJ. The diagnosis of preterm labor and the prediction of preterm delivery. Clin Obstet Gynecol 1995;38:675–87. 4. Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol 2007;197:426.e1–7. 5. Winder SJ, Walsh MP. Smooth muscle calponin: inhibition of actomyosin MgATPase and regulation by phosphorylation. J Biol Chem 1990;265:10148–55. 6. Arner A, Pfitzer G. Regulation of cross-bridge cycling by Ca2+ in smooth muscle. Rev Physiol Biochem Pharmacol 1999;134: 63–146. 7. Marston SB, Trevett RM, Walters M. Calcium ion regulated thin filaments from vascular smooth muscle. Biochem J 1980;185: 355–65. 8. Gunst SJ, al-Hassani MH, Adam LP. Regulation of isotonic shortening velocity by second messengers in tracheal smooth muscle. Am J Physiol 1994;266:C684–91. 9. Horowitz A, Menice CB, Laporte R, Morgan KG. Mechanisms of smooth muscle contraction. Physiol Rev 1996;76:967–1003. 10. Suzuki T, Distance A, Zizza A. Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection. Eur Heart J 2008;29: 1439–45.
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Y. Perlitz et al.
Downloaded by [Chinese University of Hong Kong] at 22:50 05 November 2015
11. Schiff HB, MacSearraigh ET, Kallmever JC. Myoglobinuria, rhabdomyolysis and marathon running. Q J Med 1978;188: 463–72. 12. Lindahl B. Acute coronary syndrome – the present and future role of biomarkers. Clin Chem Lab Med 2013;23:1–8. 13. Lee TH, Goldman L. Evaluation of the patient with acute chest pain. N Engl J Med 2000;342:1187–95.
J Matern Fetal Neonatal Med, 2015; 28(10): 1158–1160
14. Takahashi K, Hiwada K, Kokubu T. Vascular smooth muscle calponin. Anovel troponin T-like protein. Hypertension 1988;11: 620–6. 15. Cornwell TL, Li J, Sellak H, et al. Reorganization of myofilament proteins and decreased cGMP-dependent protein kinase in the human uterus during pregnancy. J Clin Endocrinol Metab. 2001;86: 3981–8.
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Calponin levels in term laboring women Yuri Perlitz, Moshe Ben-Ami, Aviva Peleg, Ido Izhaki & Izhar Ben-Shlomo To cite this article: Yuri Perlitz, Moshe Ben-Ami, Aviva Peleg, Ido Izhaki & Izhar Ben-Shlomo (2015) Calponin levels in term laboring women, The Journal of Maternal-Fetal & Neonatal Medicine, 28:10, 1158-1160, DOI: 10.3109/14767058.2014.947570 To link to this article: http://dx.doi.org/10.3109/14767058.2014.947570
Accepted author version posted online: 22 Jul 2014. Published online: 12 Aug 2014. Submit your article to this journal
Article views: 20
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [Chinese University of Hong Kong]
Date: 05 November 2015, At: 22:50
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(10): 1158–1160 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.947570
ORIGINAL ARTICLE
Calponin levels in term laboring women Yuri Perlitz1,2, Moshe Ben-Ami1,2, Aviva Peleg3, Ido Izhaki4, and Izhar Ben-Shlomo1,2 1
Department of OB&GYN, The Baruch Padeh Medical Center, Poriya, Israel, 2Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel, Research Laboratory, The Baruch Padeh Medical Center, Poriya, Israel, and 4Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel
Downloaded by [Chinese University of Hong Kong] at 22:50 05 November 2015
3
Abstract
Keywords
Objective: Calponin, a specific smooth muscle contraction regulatory troponin-like protein, is present in large quantities in uterine smooth muscle. Serum troponin levels rise in acute myocardial infarction, and creatine phosphokinase levels rise at high physical activity, both due to destruction of cardiac and striated muscle fibers. We hypothesize that the active labor process may cause uterine smooth muscle cell damage, which may result in rising maternal serum calponin levels. This was a preliminary study, searching for a new biomarker for preterm labor. Methods: The study group included laboring term primiparous women with a singleton fetus. The control group included similar demographic and pregnancy characteristics pregnant women not in labor. Maternal serum levels of calponin basic isoform were measured evaluated and compared in both groups. Results: Study group included 100 pregnant women. Calponin serum levels were higher in the active labor (794 ± 974 ng/mL) than in the group not in labor (591 ± 587 ng/mL), although it did not reach statistical significance. Gender and neonatal weight were similar in the two study groups. Conclusions: Calponin serum levels showed moderate elevation during active labor, compared to the levels in a cohort of pregnant comparable women at the same gestational weeks but not in labor.
Calponin, labor, pregnancy, preterm labor
Introduction Preterm labor (PTL) continues to pose a major concern in modern obstetrical practice since prematurity complications are the leading cause of perinatal morbidity and mortality [1,2]. It is often difficult to distinguish between contractions leading to cervical change and preterm birth and those which do not. Women with PTL usually require hospitalization with specific attention and therapeutic measures. On the other hand, Braxton–Hicks contractions, an un-harmful physiological phenomenon, do not require intervention [3]. Both cervical fibronectin and cervical length have been evaluated in the diagnosis of PTL, but both have low positive predictive values [4]. An accurate and rapid test, which could distinguish between the types of uterine contractions, would aid in the prevention of PTL. Smooth muscle contractions are regulated primarily by the reversible phosphorylation of myosin light chain, which is triggered by an increase in sarcoplasmic-free Ca2+ concentration. However, contractions can be modulated by other signal transduction pathways, one of which involves the thin Address for correspondence: Yuri Perlitz, MD, Department of OB&GYN, The Baruch Padeh Medical Center, Poriya, MPO Lower Galilee, 15208, Tiberias, Israel. Tel: +972-6652309. E-mail: [email protected]
History Received 9 February 2014 Accepted 19 July 2014 Published online 12 August 2014
filament-associated calponin [5]. Calponin is a thin filament, actin regulatory protein, which has three isoforms, each a product of separate genes [6–8]. Calponin was originally identified as a protein that interacts with actin and directly inhibits actin-activated Mg-ATPase activity of myosin [9,13]. We hypothesized that calponin, a smooth muscle troponinlike protein, may serve as a biomarker for diagnosing true PTL. This was based on the following facts: (1) the h1 (basic) isoform of calponin is the most abundant and specific protein of smooth muscle [10]; (2) during second and third trimesters of pregnancy, the uterus is the organ containing the largest volume of smooth muscle and therefore, calponin; and (3) serum creatine phosphokinase (CPK) rises when overuse of striated muscles occurs [11], and serum troponin rises when cardiac ischemia occurs [12,13]. The process of contractions resulting in true labor may results in myometrial destruction rising maternal serum calponin levels. In a first step to determine whether calponin h1 can be used as a biomarker for labor, we examined whether serum levels increased during active labor in term deliveries.
Methods Primiparous low-risk women included in our study were at term (37–41 weeks gestation) with a singleton fetus with no
Calponin term laboring women
DOI: 10.3109/14767058.2014.947570
Table 1. Calponin levels and other characteristics.
Age (years) Gestational week Calponin (pg/ml) Cervical dilatation (cm) Birth weight (g)
Active labor N ¼ 50
No labor N ¼ 50
Mean ± SD (n)
Mean ± SD (n)
p
28.4 ± 5.2 39.6 ± 1.1 794.8 ± 974.9 6.0 ± 1.6 3364.9 ± 461.6
31.1 ± 5.1 39.6 ± 1.0 591.3 ± 587.6 0.4 ± 0.8 3430.1 ± 486.5
50.05 NS NS 50.001 NS
Downloaded by [Chinese University of Hong Kong] at 22:50 05 November 2015
All values are expressed as mean, standard deviation.
known anomaly. We recruited two groups. The study group included women in spontaneous active labor at term defined as cervical dilatation 4 cm and 3 contractions in 10 min with intact membranes, not receiving antibiotics, oxytocin or analgesia for pain. The control group included women with the same inclusion criteria but not in labor as defined as cervical dilatation 52 cm, 52 contractions in a 10-min period and no vaginal bleeding or ruptured membranes. All study participants were non-smokers and did not consume any medications other than iron and folic acid supplementation. The study was approved by our institutional review board, and all participants gave informed consent. Serum h1 calponin concentration was measured in duplicates using ELISA (Cusabio Biotech Co., Wuhan, China). The minimum detectable value of calponin was 40 pg/ml and the maximum was 24 000 pg/ml. Statistical analysis between the groups was by student t-test. A p50.05 was considered significant.
Results Fifty women in each group were recruited to the study. Calponin levels and other relevant characteristics are listed in Table 1. There was a significant difference in the age of the two study groups. As expected, cervical dilatation was statistically different between groups at the time of blood draw. Calponin levels were higher in the active labor group than in the no labor group, although this did not reach statistical significance.
Discussion We evaluated calponin, a smooth muscle contraction regulatory protein, as a possible biomarker for labor in term patients. If calponin levels were elevated in term laboring patients, we theorized it might be a possible marker of labor in preterm women. Our hypothesis theorized that calponin may be discharged from the contracting uterine smooth muscles into the maternal serum, as a result of uterine smooth muscle fibers destruction during active labor. Our assumption was based on the observation of CPK rising levels as a result of striated muscles destruction during strenuous physical activity [11]. Furthermore, rising serum troponin levels are well established after cardiac muscles destruction as a result of a coronary event [12,13]. Our results revealed no significant difference in calponin levels in the serum of women in active labor at term compared to women not in labor. In 1988, Takahashi et al. reported for the first time the presence of calponin in bovine aorta smooth muscles [14].
1159
This 35 000 molar ratio protein function was suggested to be an additional Ca2+ regulatory component of smooth muscle thin filament. Suzuki et al. evaluated calponin as a possible biomarker for aortic dissection (AD) [10]. They included in their study 59 cases of radiographically proven acute AD and 158 controls with an initial suspicion of AD but a different final diagnosis. Of the 59 AD cases, the basic calponin isoform showed more than threefold increase for all dissections when sampled within the first six hours of symptom onset. The authors of that study concluded that basic calponin assay may improve acute AD diagnosis. Cornwell et al. tested the hypothesis that the levels and subcellular distribution of caldesmon, calponin and cGMPdependent protein kinase are regulated with the hormonal milieu of human pregnancy. Their results demonstrated that although cGMP-dependent protein kinase was significantly reduced in the human uterus during pregnancy, caldesmon expression was significantly increased, and both caldesmon and calponin were redistributed to a readily extractable subcellular pool. These data suggest that cGMP-dependent protein kinase does not mediate gestational quiescence. Redistribution of thin filament-associated proteins, however, may alter uterine smooth muscle tone or the cytoskeletal framework of myocytes to maintain gestation despite the substantial distention that accompanies all intrauterine pregnancies [15]. This is the first study to measure calponin levels in a cohort of women at term in active labor. Although we were able to demonstrate a moderate elevation of calponin levels in the laboring group, the difference was not statistically different. It would seem that calponin is not a good marker of labor at term, although a study of women with PTL is needed to conclude if the same is true in preterm women with contractions.
References 1. Heron M, Sulton PD, Xu J. Annual summary of vital statistics: 2007. Pediatrics 2010;125:4–15. 2. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75–84. 3. Lockwood CJ. The diagnosis of preterm labor and the prediction of preterm delivery. Clin Obstet Gynecol 1995;38:675–87. 4. Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol 2007;197:426.e1–7. 5. Winder SJ, Walsh MP. Smooth muscle calponin: inhibition of actomyosin MgATPase and regulation by phosphorylation. J Biol Chem 1990;265:10148–55. 6. Arner A, Pfitzer G. Regulation of cross-bridge cycling by Ca2+ in smooth muscle. Rev Physiol Biochem Pharmacol 1999;134: 63–146. 7. Marston SB, Trevett RM, Walters M. Calcium ion regulated thin filaments from vascular smooth muscle. Biochem J 1980;185: 355–65. 8. Gunst SJ, al-Hassani MH, Adam LP. Regulation of isotonic shortening velocity by second messengers in tracheal smooth muscle. Am J Physiol 1994;266:C684–91. 9. Horowitz A, Menice CB, Laporte R, Morgan KG. Mechanisms of smooth muscle contraction. Physiol Rev 1996;76:967–1003. 10. Suzuki T, Distance A, Zizza A. Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection. Eur Heart J 2008;29: 1439–45.
1160
Y. Perlitz et al.
Downloaded by [Chinese University of Hong Kong] at 22:50 05 November 2015
11. Schiff HB, MacSearraigh ET, Kallmever JC. Myoglobinuria, rhabdomyolysis and marathon running. Q J Med 1978;188: 463–72. 12. Lindahl B. Acute coronary syndrome – the present and future role of biomarkers. Clin Chem Lab Med 2013;23:1–8. 13. Lee TH, Goldman L. Evaluation of the patient with acute chest pain. N Engl J Med 2000;342:1187–95.
J Matern Fetal Neonatal Med, 2015; 28(10): 1158–1160
14. Takahashi K, Hiwada K, Kokubu T. Vascular smooth muscle calponin. Anovel troponin T-like protein. Hypertension 1988;11: 620–6. 15. Cornwell TL, Li J, Sellak H, et al. Reorganization of myofilament proteins and decreased cGMP-dependent protein kinase in the human uterus during pregnancy. J Clin Endocrinol Metab. 2001;86: 3981–8.
