Efeito de drogas utilizadas no tratamento da hipertensão e da asma na infecção e replicação do SARS-CoV-2 em cardiomiócitos
Data
2023-11-05
Autores
Pinto, Renan Novaes 
Orientadores
Maricato, Juliana Terzi
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A COVID-19 é uma doença viral, atualmente considerada sistêmica, comumente iniciada no sistema respiratório. Além deste, diversos relatos indicam efeitos neurológicos, imunológicos e, principalmente, cardíacos decorrentes da infecção pelo SARS-CoV-2. O cardiomiócito é uma célula considerada potencial alvo do vírus, pois expressa diversas moléculas importantes para o ciclo viral, como a ECA2, além de ser capaz de sustentar a replicação viral. A avaliação epidemiológica da COVID-19 indicou, logo nos primeiros relatos de surto da doença, alguns fatores de risco associados ao desenvolvimento da forma grave da doença. A idade avançada e a presença de comorbidades, como diabetes, obesidade e doenças cardíacas e respiratórias crônicas, foram indicadas como fatores de risco de alerta, com altas taxas de mortalidade por COVID-19. Dessa forma, esta dissertação teve como objetivo avaliar, in vitro, o efeito do uso regular de propranolol e salbutamol, utilizados comumente para o tratamento da hipertensão e asma, respectivamente, durante a infecção por SARS-CoV-2 em cardiomiócitos derivados de células tronco pluripotentes humanas induzidas (hiPSC). Assim, avaliou-se a suscetibilidade viral dos cardiomiócitos, a citotoxicidade das drogas de interesse utilizadas, a replicação viral e os efeitos sobre a integridade e função celular e a produção de citocinas durante a infecção e tratamento. Em seguida, comparou-se a expressão de citocinas entre cardiomiócitos hiPSC, obtidos e infectados in vitro, com a de cardiomiócitos obtidos de camundongos transgênicos (expressando ECA2 humana) e infectados in vivo com SARS-CoV-2. Por fim, observou-se um potencial cardioprotetor do propranolol durante a infecção pelo SARS-CoV-2 por meio da diminuição da expressão de receptores virais e o aumento na expressão de citocinas antivirais nos cardiomiócitos. O salbutamol, por sua vez, apresentou efeito potencialmente contrário, com aumento da carga viral no sobrenadante celular e diminuição de citocinas de antivirais.
COVID-19 is a viral disease, currently considered systemic, commonly initiated in the respiratory system. In addition to this, several reports indicate neurological, immunological and, mainly, cardiac effects resulting from SARS-CoV-2 infection. The cardiomyocyte is a cell considered a potential target for the virus, as it expresses several important molecules for the viral cycle, such as ACE2, in addition to being capable of sustaining viral replication. The epidemiological evaluation of COVID-19 indicated, in the first reports of an outbreak of the disease, some risk factors associated with the development of the severe form of the disease. Advanced age and the presence of comorbidities such as diabetes, obesity, and chronic heart and respiratory diseases have been indicated as risk factors for alerting, with high mortality rates from COVID-19. Thus, the present study aimed to evaluate, in vitro, the effect of regular use of propranolol and salbutamol, commonly used for the treatment of hypertension and asthma, respectively, during SARS-CoV-2 infection in cardiomyocytes derived from stem cells human induced pluripotent cells (hiPSC). Thus, we evaluated the viral susceptibility of cardiomyocytes, the cytotoxicity of the drugs of interest used, viral replication and the effects on cellular integrity and function and the production of cytokines during infection and treatment. Next, cytokine expression was compared between hiPSC cardiomyocytes, obtained and infected in vitro, with that of cardiomyocytes obtained from transgenic mice (expressing human ACE2) and infected in vivo with SARS-CoV-2. Finally, a cardioprotective potential of propranolol during SARS-CoV-2 infection was observed through the decrease in the expression of viral receptors and the increase in the expression of antiviral cytokines in cardiomyocytes. Salbutamol, in turn, had a potentially opposite effect, with an increase in viral load in the cell supernatant and a decrease in antiviral cytokines.
COVID-19 is a viral disease, currently considered systemic, commonly initiated in the respiratory system. In addition to this, several reports indicate neurological, immunological and, mainly, cardiac effects resulting from SARS-CoV-2 infection. The cardiomyocyte is a cell considered a potential target for the virus, as it expresses several important molecules for the viral cycle, such as ACE2, in addition to being capable of sustaining viral replication. The epidemiological evaluation of COVID-19 indicated, in the first reports of an outbreak of the disease, some risk factors associated with the development of the severe form of the disease. Advanced age and the presence of comorbidities such as diabetes, obesity, and chronic heart and respiratory diseases have been indicated as risk factors for alerting, with high mortality rates from COVID-19. Thus, the present study aimed to evaluate, in vitro, the effect of regular use of propranolol and salbutamol, commonly used for the treatment of hypertension and asthma, respectively, during SARS-CoV-2 infection in cardiomyocytes derived from stem cells human induced pluripotent cells (hiPSC). Thus, we evaluated the viral susceptibility of cardiomyocytes, the cytotoxicity of the drugs of interest used, viral replication and the effects on cellular integrity and function and the production of cytokines during infection and treatment. Next, cytokine expression was compared between hiPSC cardiomyocytes, obtained and infected in vitro, with that of cardiomyocytes obtained from transgenic mice (expressing human ACE2) and infected in vivo with SARS-CoV-2. Finally, a cardioprotective potential of propranolol during SARS-CoV-2 infection was observed through the decrease in the expression of viral receptors and the increase in the expression of antiviral cytokines in cardiomyocytes. Salbutamol, in turn, had a potentially opposite effect, with an increase in viral load in the cell supernatant and a decrease in antiviral cytokines.