Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.

RATIONALE: Yes-associated protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation. OBJECTIVE: We hypothesized that YAP activation after myocardial infarction (MI) would preserve cardiac function and improve survival. METHODS AND RESULTS: We used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after MI preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP (hYAP) in the adult murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated expression of cell cycle genes and promoted a less mature cardiac gene expression signature. CONCLUSIONS: Cardiac-specific YAP activation after MI mitigated myocardial injury, improved cardiac function, and enhanced survival. These findings suggest that therapeutic activation of YAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI.

YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy.

Heart growth is tightly controlled so that the heart reaches a predetermined size. Fetal heart growth occurs through cardiomyocyte proliferation, whereas postnatal heart growth involves primarily physiological cardiomyocyte hypertrophy. The Hippo kinase cascade is an important regulator of organ growth. A major target of this kinase cascade is YAP1, a transcriptional coactivator that is inactivated by Hippo kinase activity. Here, we used both genetic gain and loss of Yap1 function to investigate its role in regulating proliferative and physiologic hypertrophic heart growth. Fetal Yap1 inactivation caused marked, lethal myocardial hypoplasia and decreased cardiomyocyte proliferation, whereas fetal activation of YAP1 stimulated cardiomyocyte proliferation. Enhanced proliferation was particularly dramatic in trabecular cardiomyocytes that normally exit from the cell cycle. Remarkably, YAP1 activation was sufficient to stimulate proliferation of postnatal cardiomyocytes, both in culture and in the intact heart. A dominant negative peptide that blocked YAP1 binding to TEAD transcription factors inhibited YAP1 proliferative activity, indicating that this activity requires YAP1-TEAD interaction. Although Yap1 was a critical regulator of cardiomyocyte proliferation, it did not influence physiological hypertrophic growth of cardiomyocytes, because postnatal Yap1 gain or loss of function did not significantly alter cardiomyocyte size. These studies demonstrate that Yap1 is a crucial regulator of cardiomyocyte proliferation, cardiac morphogenesis, and myocardial trabeculation. Activation of Yap1 in postnatal cardiomyocytes may be a useful strategy to stimulate cardiomyocyte expansion in therapeutic myocardial regeneration.

Cervical length in adolescents versus adults.

PURPOSE: Two of the known risk factors for spontaneous preterm birth (sPTB) are short cervical length (CL) ≤ 25 mm and adolescence (≤19 years). Our objective was to evaluate whether adolescent women have a higher incidence of short CL compared to their 20-24 year old counterparts. MATERIALS AND METHODS: Retrospective cohort of nulliparous singleton gestations undergoing universal second trimester transvaginal ultrasound (TVU) CL screening between January 2012 and June 2013. Adolescent women ≤19 years of age were compared to women 20-24 years of age. Primary outcomes were mean CL and incidence of CL ≤25 mm. Secondary outcomes were incidence of PTB <37 weeks, delivery mode, birth weight, and NICU admission. RESULTS: One hundred and five adolescents and 236 women 20-24 years underwent TVU CL screening. There was no difference in mean CL (40.6 mm vs. 40.6 mm, p = 0.51) or incidence of CL ≤25 mm (1.0% vs. 1.7%; OR 0.56 [0.06-5.1]). After controlling for maternal differences, there still was no significant correlation between maternal age and CL. There was no significant difference in PTB, birth weight, or NICU admission between the groups. CL measurements did not significantly differ across all maternal ages (14-42 years). CONCLUSIONS: There is no difference in mean CL or incidence of CL ≤25 mm among adolescents compared to women 20-24 years.

Racial disparities in cervical length for prediction of preterm birth in a low risk population.

PURPOSE: Racial minorities experience higher rates of spontaneous preterm birth (sPTB). Our objective was to evaluate whether there are racial discrepancies in the incidence of second trimester short cervical length (≤25 mm). MATERIALS AND METHODS: Retrospective cohort of women with singleton gestations without prior sPTB undergoing universal second trimester transvaginal ultrasound cervical length (CL) screening between January 2012 and December 2013. Black women were compared to non-Hispanic white women. Our primary outcome was the incidence of CL ≤25 mm. Secondary outcomes were incidence of PTB ≤37 weeks, delivery mode, birth weight and neonatal intensive care unit (NICU) admission. RESULTS: Black women (n = 1092) differed from non-Hispanic white women (n = 659) with respect to maternal age (26.0 versus 30.7 years), gravidity (3.1 versus 2.1), prepregnancy BMI (29.6 versus 25.0 kg/m2), and smoking status (9.8% versus 16%), respectively (p < 0.001). Black women had higher incidence of CL ≤25 mm (1.9% versus 0.6%; OR: 3.21 [1.1-9.4]), rates of sPTB (8.5% versus 4.4%; aOR: 1.95 [1.1-3.4]), incidence of low birthweight infants (<2500 g, 8.3% versus 5.6%; aOR 1.80 [1.1-3.0]) and were more likely to have their infants admitted to the NICU (16% versus 11%; OR: 1.52 [1.0-2.3]). CONCLUSIONS: Black women had a 2.8-fold increased risk of CL ≤25 mm compared non-Hispanic white women in a low-risk population.