Increased Reactive Oxygen Species, Metabolic Maladaptation, and Autophagy Contribute to Pulmonary Arterial Hypertension–Induced Ventricular Hypertrophy and Diastolic Heart Failure

Abstract

Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease with no known cure. Heart failure is a major comorbidity and a common cause of the premature death of patients with PAH. Increased asymmetrical right ventricular hypertrophy and septal wall thickening compress the left ventricular cavity and elicit diastolic heart failure. In this study, we used the Sugen5416/hypoxia/normoxia-induced PAH rat to determine whether altered pyridine nucleotide signaling in the failing heart contributes to 1) increased oxidative stress, 2) changes in metabolic phenotype, 3) autophagy, and 4) the PAH-induced failure. We found that increased reactive oxygen species, metabolic maladaptation, and autophagy contributed to the pathogenesis of right ventricular remodeling and hypertrophy that lead to left ventricular diastolic dysfunction. In addition, arterial elastance increased in PAH rats. Glucose-6-phosphate dehydrogenase is a major source of pyridine molecule (nicotinamide adenine dinucleotide phosphate), which is a substrate for nicotinamide adenine dinucleotide phosphate oxidases in the heart. Dehydroepiandrosterone, a 17-ketosteroid that reduces pulmonary hypertension and right ventricular hypertrophy, inhibited glucose-6-phosphate dehydrogenase, decreased oxidative stress, increased glucose oxidation and acetyl-coA, and reduced autophagy in the hearts of PAH rats. It also decreased arterial stiffness and improved left ventricular diastolic function. These findings demonstrate that pyridine nucleotide signaling, at least partly, mediates PAH-induced diastolic heart failure, and that reduction of glucose-6-phosphate dehydrogenase-derived nicotinamide adenine dinucleotide phosphate is beneficial to improve left ventricle diastolic function.

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).…”

“…In the failing hearts, oxidative stress is increased and the rate of cardiomyocyte apoptotic and autophagic death is augmented (6,49,51,60,62). Activation of these processes causes myocardial stiffening, dilatation, and loss of contractility (49, 51).…”

17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension

“…Second, while we demonstrate favorable effects of endogenous or exogenous E 2 on proapoptotic signaling, eNOS phosphorylation, and autophagic flux, these parameters were not significantly affected by SuHx or sex. While this may suggest that these pathways do not play a role in RV failure, this is unlikely in light of previously published data that demonstrate pathophysiological relevance (6,14,29,46,47,52). A more likely explanation is that the present studies were underpowered to detect more profound changes in these endpoints.…”

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

“…G6PD inhibition relaxes pulmonary arteries by decreasing intracellular calcium (20), prevents switching of vascular smooth muscle cells to a synthetic phenotype (9,10), and reduces pulmonary hypertension (9,47). However, whether prolonged hypoxia-induced 20-HETE-synthesis is G6PD dependent or independent and whether G6PD modulates 20-HETE signaling in the vascular smooth muscle remain unknown.…”