Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies.

Pulmonary arterial hypertension (PAH) is a malignant disease with high mortality and closely involves the bone morphogenetic protein (BMP) pathway. Mutations in BMPR2 caused proliferation of pulmonary artery smooth muscle cells (PASMCs) leading to PAH. Isorhamnetin, one of the main naturally occurring flavonoids extracted from Hippophae rhamnoides L, shows antiinflammatory and anti-proliferative properties. Nevertheless, the effects of isorhamnetin on PAH remain unclear. This study aimed to investigate whether isorhamnetin has protective effects against PAH and explore possible mechanisms. An in vivo model of PAH induced by monocrotaline (MCT) was employed, and sildenafil and isorhamnetin were orally administered for 21 consecutive days. An in vitro model induced by TNF-α was employed, and cell proliferation of HPASMCs was detected. Results indicated that isorhamnetin significantly improved hemodynamic, histopathological, and echocardiographic changes in MCT-induced PAH in rats. In vitro, isorhamnetin suppressed TNF-α-induced HPASMCs proliferation. Furthermore, isorhamnetin improved protein expression of BMPR2 and suppressed protein expression of TNF-α and IL-6 in rat lungs. Isorhamnetin improved protein expression of BMPR2 and p-smad1/5 and mRNA expression of Id1 and Id3 in HPASMCs. Isorhamnetin ameliorated MCT-induced PAH in rats and inhibited TNF-α-induced HPASMCs proliferation by a mechanism likely involving the regulation of the BMP signaling pathway.

Methyl 2-[2-(6-chloro-pyrimidin-4-yl-oxy)phen-yl]-3,3-dimethoxy-propanoate.

In the title compound, C(16)H(17)ClN(2)O(5), the dihedral angle between the aromatic rings is 77.36 (4)°. An intra-molecular C-H⋯O inter-action results in the formation of a planar [r.m.s. deviation = 0.103 (2) Å] five-membered ring, which is oriented at a dihedral angle of 4.84 (4)° with respect to the adjacent benzene ring. In the crystal structure, weak intermolecular C-H⋯π inter-actions are found.

1-(4-Fluoro-phen-yl)-5-(4-methoxy-phen-yl)pyrazolidin-3-one.

In the mol-ecule of the title compound, C(16)H(15)FN(2)O(2), the benzene rings are oriented at a dihedral angle of 88.61 (3)°. The five-membered ring adopts an envelope conformation. Intra-molecular C-H⋯N hydrogen bonds result in the formation of two planar five-membered rings. In the crystal structure, inter-molecular N-H⋯O and C-H⋯F hydrogen bonds link the mol-ecules, forming R(2) (2)(8) and R(2) (2)(18) ring motifs. Weak C-H⋯π inter-actions may further stabilize the structure.

2-Bromo-1-mesitylethanone.

In the mol-ecule of the title compound, C(11)H(13)BrO, the adjacent C atoms are almost coplanar with the aromatic ring [maximum deviation 0.035 (3) Å]. In the crystal structure, weak inter-molecular C-H⋯O inter-actions link the mol-ecules into chains along the b axis. A very weak C-H⋯π inter-action is also present.