Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Grazielle Fernandes Silva; Jaqueline Soares da Silva; Allan Kardec Nogueira de Alencar; Marina de Moraes Carvalho da Silva; Tadeu Lima Montagnoli; Bruna de Souza Rocha; Rosana Helena Coimbra Nogueira de Freitas; Roberto Takashi Sudo; Carlos Alberto Manssour Fraga; Gisele Zapata-Sudo

doi:10.3390/ph15070900

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Pharmaceuticals (Basel). 2022 Jul 21;15(7):900. doi: 10.3390/ph15070900.

Authors

Grazielle Fernandes Silva^{1

2}, Jaqueline Soares da Silva^{1

2}, Allan Kardec Nogueira de Alencar¹, Marina de Moraes Carvalho da Silva^{1

3}, Tadeu Lima Montagnoli^{1

3}, Bruna de Souza Rocha^{1

2}, Rosana Helena Coimbra Nogueira de Freitas¹, Roberto Takashi Sudo^{1

3}, Carlos Alberto Manssour Fraga^{1

3}, Gisele Zapata-Sudo^{1

2

3}

Affiliations

¹ Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
² Programa de Pós-Graduação em Cardiologia, Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil.
³ Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.

Abstract

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.

Keywords: MAPK inhibitor; SU5416/hypoxia; inflammation; pulmonary hypertension; right ventricle failure.

Grants and funding

This research was funded by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro—FAPERJ, (# E-26/200.881/2021); Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos—INCT-INOFAR.