RESUMEN
Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.
Asunto(s)
Canales de Calcio/genética , Cardiomiopatías/tratamiento farmacológico , Proteínas del Choque Térmico HSP20/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Probenecid/farmacología , Canales Catiónicos TRPV/genética , Animales , Apoptosis/efectos de los fármacos , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/genética , Cardiomiopatías/patología , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Ratones , Mutación/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Periodo Periparto/efectos de los fármacos , Embarazo , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Complicaciones Cardiovasculares del Embarazo/genéticaRESUMEN
The myocardial response to exercise is an adaptive mechanism that permits the heart to maintain cardiac output via improved cardiac function and development of hypertrophy. There are many overlapping mechanisms via which this occurs with calcium handling being a crucial component of this process. Our laboratory has previously found that the stretch sensitive TRPV2 channels are active regulators of calcium handling and cardiac function under baseline conditions based on our observations that TRPV2-KO mice have impaired cardiac function at baseline. The focus of this study was to determine the cardiac function of TRPV2-KO mice under exercise conditions. We measured skeletal muscle at baseline in WT and TRPV2-KO mice and subjected them to various exercise protocols and measured the cardiac response using echocardiography and molecular markers. Our results demonstrate that the TRPV2-KO mouse did not tolerate forced exercise although they became increasingly exercise tolerant with voluntary exercise. This occurs as the cardiac function deteriorates further with exercise. Thus, our conclusion is that TRPV2-KO mice have impaired cardiac functional response to exercise.
