Subamnex Ameliorates Hypoxia-Induced Pulmonary Arterial Hypertension through Modulation of the STAT3/p-STAT3 Pathway

Pulmonary arterial hypertension (PAH) is a devastating
disease
characterized by progressive vascular remodeling and elevated pulmonary
pressure, leading to right heart failure and high mortality, against
which current treatments are limited and mechanisms remain incompletely
understood. In this medicinal chemistry study, we designed, synthesized,
and evaluated nine naphthalimide-polyamine derivatives (7a–7c, 12a–12b, 17a–17c and Subamnex) by taking
advantage of the unique chemical structure and potential biological
activity of polyamine derivatives. Our results demonstrate that the
symmetrical polyamine azo-naphthalimide naphthalimide-polyamine derivatives,
named Subamnex, suppresses pathological pulmonary arterial smooth
muscle cells (PASMCs) proliferation and migration by targeting IL-6-induced
STAT3 phosphorylation. By regulating key downstream effectors including
NEAT1, Pim-1, and the Bax/Bcl-2 balance to attenuate remodeling, our
work proposes a novel strategy to reverse vascular remodeling beyond
symptom alleviation.