Zebrafish Heart Failure Models for the Evaluation of Chemical Probes and Drugs

Abstract

Heart failure is a complex disease that involves genetic, environmental, and physiological factors. As a result, current medication and treatment for heart failure produces limited efficacy, and better medication is in demand. Although mammalian models exist, simple and low-cost models will be more beneficial for drug discovery and mechanistic studies of heart failure. We previously reported that aristolochic acid (AA) caused cardiac defects in zebrafish embryos that resemble heart failure. Here, we showed that cardiac troponin T and atrial natriuretic peptide were expressed at significantly higher levels in AA-treated embryos, presumably due to cardiac hypertrophy. In addition, several human heart failure drugs could moderately attenuate the AA-induced heart failure by 10%-40%, further verifying the model for drug discovery. We then developed a drug screening assay using the AA-treated zebrafish embryos and identified three compounds. Mitogen-activated protein kinase kinase inhibitor (MEK-I), an inhibitor for the MEK-1/2 known to be involved in cardiac hypertrophy and heart failure, showed nearly 60% heart failure attenuation. C25, a chalcone derivative, and A11, a phenolic compound, showed around 80% and 90% attenuation, respectively. Time course experiments revealed that, to obtain 50% efficacy, these compounds were required within different hours of AA treatment. Furthermore, quantitative polymerase chain reaction showed that C25, not MEK-I or A11, strongly suppressed inflammation. Finally, C25 and MEK-I, but not A11, could also rescue the doxorubicin-induced heart failure in zebrafish embryos. In summary, we have established two tractable heart failure models for drug discovery and three potential drugs have been identified that seem to attenuate heart failure by different mechanisms.

A Novel Stilbene-Like Compound That Reduces Melanin through Inhibiting Melanocyte Differentiation and Proliferation without Inhibiting Tyrosinase

“…MoTP has been shown to cause melanocyte cell death in a tyrosinase-dependent manner (Yang et al [21]). MEK-I is interesting in that it caused notochord development defects ( Figure 1, Hawkins et al [22], Huang et al [16]), but only in early embryos. PTU also cause notochord distortion in early embryos, presumably due to its ability to chelate copper ions (also reported in Hawkins et al [22].…”

“…Cosmetics 2018, 5, x FOR PEER REVIEW 3 of 14 Our lab has been using an established zebrafish heart failure model (Huang et al [16]) to look for compounds that could attenuate heart failure progression. Among the several positive compounds that were identified in the last few years, A11 and MEK-I were also able to cause significant reduction of black pigment in the zebrafish embryos.…”

Recent progress in the use of zebrafish for novel cardiac drug discovery

“…Thus, incubation with Doxorubicin has proven as an excellent method for the induction of cardiomyopathy and heart failure in embryonic zebrafish within 4 days and adult zebrafish within 4 weeks after application to serve as a model for chronic heart failure [83,84]. Furthermore, zebrafish embryos treated with aristolochic acid develop cardiac hypertrophy and acute progression of heart failure eventually resulting in cessation of cardiac contractions 2 days after treatment [84,85]. This model was further validated by challenge with human heart failure drugs such as the b-blocker metoprolol and the ACE-inhibitor captopril, which attenuated heart failure in the aristolochic acid-treated zebrafish embryos [84].…”

“…This model was further validated by challenge with human heart failure drugs such as the b-blocker metoprolol and the ACE-inhibitor captopril, which attenuated heart failure in the aristolochic acid-treated zebrafish embryos [84]. By a SCS using both heart failure models and three small chemical libraries, Huang et al identified three drugs (mitogen-activated protein kinase inhibitor MEK-I, the chalacone derivate C25 and the phenolic compound A-11) that were able to suppress the heart failure phenotype in both, Doxorubicin and aristolochic acid-treated zebrafish embryos [85], suggesting that these compounds might target common pathways involved in heart failure.…”

Use of Coronary Ultrasound Imaging to Evaluate Ventricular Function in Adult Zebrafish

“…Zebrafish embryos also offer the opportunity to test a variety of molecules through high throughput screening to facilitate the development of new therapies. 2,3 Although zebrafish embryos are outstanding as an in vivo model and have unique genetic tools, many human cardiovascular diseases occur at adulthood with a progressive pathogenesis. As such, the adult zebrafish model has been studied for its ability to model human cardiovascular diseases.…”