The role of 5-HT2B receptors in development of valvulopathy, cardiomyopathy, and pulmonary hypertension in Fawn-Hooded rats

Abstract

Patients with serotonin interference and carcinoid syndrome producing hyperserotoninaemia are prone to develop cardiac valvulopathies. Elevated serotonin levels have also been linked to pulmonary hypertension (PH) via induction of pulmonary vasoconstriction and proliferation of pulmonary artery smooth muscle cells. Fawn-Hooded rats were used, which genetically exhibit a platelet storage pool disease, hence are unable to store serotonin in platelets. In vivo hemodynamic measurements (Millar catheter) were used to characterize pulmonary artery systolic pressure (PAPs) along with echocardiographic examination. Cardiac fibrosis was evaluated by Masson's trichrome staining. Serotonin receptor expression was measured by qRT-PCR. Proliferation and serotonin receptor expression in response to various stimulations were evaluated in cultured cardiac fibroblasts. Fawn-Hooded rats presented with elevated PAPs starting at three months of age compared to age-matched control Brown Norway rats. Once developed, elevated PAPs did not further deteriorate. PH was reduced by treatment with the 5-HT2B inhibitor terguride, as evidenced by normalised right ventricle-body weight ratio (a marker of right ventricular hypertrophy), PAPs and pulmonary acceleration time (echocardiography). Histology revealed progressive valvulopathy with inappropriate presence of chondrocytes and fibrosis in the aortic and mitral valves in Fawn-Hooded rats. Progressive fibrosis did not limit to the valves, but pervaded left ventricular (LV) myocardial interstitium. These findings were associated with increased transaortic gradient, a marker of aortic stenosis, progressive LV dilation with systolic/diastolic impairment, evaluated by echocardiography. In response to serotonin and fetal calf serum Brown Norway-derived cardiac fibroblasts showed increased proliferation and upregulation of 5-HT2B receptor (RT-PCR), which was reversible with terguride. Fawn-Hooded rats developed both PH and cardiac valvulopathy. Both PH and cardiac valvulopathy were attenuated by treatment with the 5-HT2B antagonist terguride.