Emerging Metabolic Therapies in Pulmonary Arterial Hypertension

Harvey, Lloyd D.; Chan, Stephen Y.

doi:10.3390/jcm6040043

Cited by 44 publications

(32 citation statements)

References 197 publications

(261 reference statements)

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“…Like in cancer cells, the mitochondria in PH exhibit hyperpolarized membrane potential and thus resistance to apoptosis (25,26,28). These metabolic perturbations, summarized in Figure 1, have reframed our understanding of PH pathogenesis (2) and are a basis for the "metabolic theory" of this disease -a concept discussed in recent reviews (29)(30)(31). While the Warburg effect has served as a conceptual anchor, the complexities of metabolic reprogramming and mitochondrial dysfunction have become the focus of intensive investigation in PH.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

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Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the "mountains" of obstacles in this field and elucidate these fundamental tenets of pulmonary vascular metabolism, such work has the potential to usher in much-needed diagnostic and therapeutic approaches for the mitochondrial and metabolic management of PH.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

Self Cite

112

110

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“…Increased glycolysis and anaplerosis provides supplementary biomass for cellular proliferation in early PAH. Increased anaplerosis could lead to a reduction in oxidative phosphorylation and cause mitochondrial dysfunction [11]. Two weeks of sugen/hypoxia increased PGC-1α expression in lung tissue, representing impairment in mitochondrial function and mitochondria biogenesis demand.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

et al. 2020

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Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder instigated by pulmonary vascular cell proliferation. Activation of Akt was previously reported to promote vascular remodeling. Also, the irreversible nitration of Y350 residue in Akt results in its activation. NitroAkt was increased in PAH patients and the SU5416/Hypoxia (SU/Hx) PAH model. This study investigated whether the prevention of Akt nitration in PAH by Akt targeted nitroxide-conjugated peptide (NP) could reverse vascular remodeling and metabolic reprogramming. Treatment of the SU/Hx model with NP significantly decreased nitration of Akt in lungs, attenuated right ventricle (RV) hypertrophy, and reduced RV systolic pressure. In the PAH model, Akt-nitration induces glycolysis by activation of the glucose transporter Glut4 and lactate dehydrogenase-A (LDHA). Decreased G6PD and increased GSK3β in SU/Hx additionally shunted intracellular glucose via glycolysis. The increased glycolytic rate upregulated anaplerosis due to activation of pyruvate carboxylase in a nitroAkt-dependent manner. NP treatment resolved glycolytic switch and activated collateral pentose phosphate and glycogenesis pathways. Prevention of Akt-nitration significantly controlled pyruvate in oxidative phosphorylation by decreasing lactate and increasing pyruvate dehydrogenases activities. Histopathological studies showed significantly reduced pulmonary vascular proliferation. Based on our current observation, preventing Akt-nitration by using an Akt-targeted nitroxide-conjugated peptide could be a useful treatment option for controlling vascular proliferation in PAH.

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“…The adaptive remodeling process is characterized by RV changes in mechanics as well as structure (e.g. myocollagen fiber orientation) (Hill et al, ), fibrosis (Andersen, Nielsen‐Kudsk, Vonk Noordegraaf, & de Man, ), vascular changes, and metabolic dysfunction (Harvey & Chan, ). Ultimately though, when the RV contractility is no longer able to accommodate an increase in afterload, the remodeling is considered to become maladaptive (Sanz et al, ; Vanderpool et al, ) and is a precursor for bad outcomes resulting in RV failure and an increase in mortality (Vanderpool et al, ).…”

Section: Introductionmentioning

confidence: 99%

The left ventricle undergoes biomechanical and gene expression changes in response to increased right ventricular pressure overload

et al. 2020

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Pulmonary hypertension (PH) results in right ventricular (RV) pressure overload and eventual failure. Current research efforts have focused on the RV while overlooking the left ventricle (LV), which is responsible for mechanically assisting the RV during contraction. The objective of this study is to evaluate the biomechanical and gene expression changes occurring in the LV due to RV pressure overload in a mouse model. Nine male mice were divided into two groups: (a) pulmonary arterial banding (PAB, N = 4) and (b) sham surgery (Sham, N = 5). Tagged and steady-state free precision cardiac MRI was performed on each mouse at 1, 4, and 7 weeks after surgery.At/week7, the mice were euthanized following right/left heart catheterization with RV/LV tissue harvested for histology and gene expression (using RT-PCR) studies.Compared to Sham mice, the PAB group revealed a significantly decreased LV and RV ejection fraction, and LV maximum torsion and torsion rate, within the first week after banding. In the PAB group, there was also a slight but significant increase in LV perivascular fibrosis, which suggests elevated myocardial stress. LV fibrosis was also accompanied with changes in gene expression in the hypertensive group, which was correlated with LV contractile mechanics. In fact, principal component (PC) analysis of LV gene expression effectively separated Sham and PAB mice along PC2. Changes in LV contractile mechanics were also significantly correlated with unfavorable changes in RV contractile mechanics, but a direct causal relationship

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Emerging Metabolic Therapies in Pulmonary Arterial Hypertension

Cited by 44 publications

References 197 publications

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

The left ventricle undergoes biomechanical and gene expression changes in response to increased right ventricular pressure overload

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