Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension

Abstract

Current therapy of pulmonary arterial hypertension (PAH) is inadequate. Dehydroepiandrosterone (DHEA) effectively treats experimental pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. Contrary to these animal models, SU5416/hypoxia/normoxia-exposed rats develop a more severe form of occlusive pulmonary arteriopathy and right ventricular (RV) dysfunction that is indistinguishable from the human disorder. Thus, we tested the effects of DHEA treatment on PAH and RV structure and function in this model. Chronic (5 wk) DHEA treatment significantly, but moderately, reduced the severely elevated RV systolic pressure. In contrast, it restored the impaired cardiac index to normal levels, resulting in an improved cardiac function, as assessed by echocardiography. Moreover, DHEA treatment inhibited RV capillary rarefaction, apoptosis, fibrosis, and oxidative stress. The steroid decreased NADPH levels in the RV. As a result, the reduced reactive oxygen species production in the RV of these rats was reversed by NADPH supplementation. Mechanistically, DHEA reduced the expression and activity of Rho kinases in the RV, which was associated with the inhibition of cardiac remodeling-related transcription factors STAT3 and NFATc3. These results show that DHEA treatment slowed the progression of severe PAH in SU5416/hypoxia/normoxia-exposed rats and protected the RV against apoptosis and fibrosis, thus preserving its contractile function. The antioxidant activity of DHEA, by depleting NADPH, plays a central role in these cardioprotective effects.

MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.

“…RVSP in the control and PAH rats was positively correlated with the respective RV/LVϩS. Consistent with our previous studies (2,49), the PAH rats were not in dilated cardiomyopathy stage at either 8 or 13 wk.…”

“…Consistently, studies show that miR-140 plays a role in promoting cardiomyocyte apoptosis by suppressing the expression of MFN1, and knockdown of miR-140 reduces myocardial infarct size (35). Previously, others and we have shown that apoptosis and autophagy/mitophagy are increased in the RV of PAH rats (2,49) and of mice with pulmonary artery banding (48), suggesting a decline of myocardial function. Mitochondria constantly undergo fusion and fission to maintain organelle homeostasis (28,30), and abnormality in this phenomenon triggers apoptotic cell death (47).…”

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

“…tive hypertrophy to maladaptive hypertrophy with clear evidence of cardiac fibrosis and dysfunction. 52,53 It has recently been shown that inhibition of SphK1/S1P signaling ameliorates infarction-induced cardiac remodeling and dysfunction, 54 and our finding of improvement in cardiac function after SphK1 inhibition without decreases in RVSP and RV hypertrophy might be attributable to a direct therapeutic benefit in maladaptive RV hypertrophy. Another factor is the short therapeutic window (3 weeks).…”

Detrimental Impact of Vasopressin V2 Receptor Antagonism in a SU5416/Hypoxia/Normoxia-Exposed Rat Model of Pulmonary Arterial Hypertension

“…A recent study demonstrated that this rat model develops very severe occlusive PAH and severe RV dysfunction, with evidence of cardiomyocyte enlargement, apoptosis, and collagen deposition during 8 weeks after a SU5416 injection. 18 To evaluate the effects of long-term V2R antagonism on pulmonary circulation and RV remodeling in much more advanced right heart failure, we decided to use SUHx rats at 9-10 weeks after a SU5416 injection.…”

“…Right ventricular (RV) wall thickness, RV end diastolic diameter, inferior vena cava (IVC), pulmonary arterial acceleration time/ejection time (PAAT/ET), and TAPSE were measured as described previously. 18 Dopplerderived RV cardiac output (RVCO) was also calculated. 19 Each parameter was averaged over 3 cardiac cycles.…”