Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension

We present evidence for time- and location-specific changes in SMC proliferation in various animal models of PH; we highlight the transient nature (rather than continuous) of SMC proliferation, emphasizing that the heterogenic SMC populations that reside in different locations along the pulmonary vascular tree exhibit distinct responses to the stresses associated with the development of PH. We also consider that cells that have often been termed ‘SMCs’ may arise from many origins, including endothelia l cells, fibroblasts and resident or circulating progenitors, and thus may contribute via distinct signalling pathways to the remodelling process. Ultimately, PH is characterized by long-lived, apoptosis-resistant SMC. In line with this key pathogenic characteristic, we address the acquisition of a pro-inflammatory phenotype by SMC that is essential to the development of PH. We present evidence that metabolic alterations akin to those observed in cancer cells (cytoplasmic and mitochondrial) directly contribute to the phenotype of the SM and SM-like cells involved in PH. Finally, we raise the p ossibility that SMCs transition from a proliferative to a senescent, pro-inflammatory and metabolically active phenotype over time.
Source: Cardiovascular Research - Category: Cardiology Source Type: research

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Publication date: Available online 8 January 2020Source: Redox BiologyAuthor(s): Jennifer L. Larson-Casey, Chao He, A.Brent CarterAbstractMechanisms underlying the pathogenesis of pulmonary fibrosis remain incompletely understood. Emerging evidence suggests changes in mitochondrial quality control are a critical determinant in many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, pulmonary hypertension, acute lung injury, lung cancer, and in the susceptibility to pulmonary fibrosis. Once thought of as the kidney-bean shaped powerhouses of the cell, mitochondria are now known to form interconne...
Source: Redox Biology - Category: Biology Source Type: research
This study demonstrated that the incidence of ischemic heart disease and death were three times higher among men with low birth weight compared to men with high birth weight (5). Epidemiological investigations of adults born at the time of the Dutch famine between 1944 and 1945 revealed an association between maternal starvation and a low infant birth weight with a high incidence of hypertension and coronary heart disease in these adults (23). Furthermore, Painter et al. reported the incidence of early onset coronary heart disease among persons conceived during the Dutch famine (24). In that regard, Barker's findin...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
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 “mounta...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Abstract 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...
Source: Clinical Lung Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research
We present a state-of-the-art review of the role of mitochondria in both the pathobiology of pulmonary hypertension and potential therapeutic targets in pulmonary vascular processes. PMID: 29345195 [PubMed - as supplied by publisher]
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research
We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capaci...
Source: Science Translational Medicine - Category: Biomedical Science Authors: Tags: Research Articles Source Type: research
Authors: Plecitá-Hlavatá L, D'alessandro A, El Kasmi K, Li M, Zhang H, Ježek P, Stenmark KR Abstract Pulmonary hypertension is a complex disease of the pulmonary vasculature, which in severe cases terminates in right heart failure. Complex remodeling of pulmonary arteries comprises the central issue of its pathology. This includes extensive proliferation, apoptotic resistance and inflammation. As such, the molecular and cellular features of pulmonary hypertension resemble hallmark characteristics of cancer cell behavior. The vascular remodeling derives from significant metabolic changes in resident c...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Journal of Cellular Physiology - Category: Cytology Authors: Tags: REVIEW ARTICLE Source Type: research
Authors: Bravo-Sagua R, Parra V, López-Crisosto C, Díaz P, Quest AF, Lavandero S Abstract Calcium (Ca2+) is a key player in the regulation of many cell functions. Just like Ca2+, mitochondria are ubiquitous, versatile, and dynamic players in determining both cell survival and death decisions. Given their ubiquitous nature, the regulation of both is deeply intertwined, whereby Ca2+ regulates mitochondrial functions, while mitochondria shape Ca2+ dynamics. Deregulation of either Ca2+ or mitochondrial signaling leads to abnormal function, cell damage or even cell death, thereby contributing to muscle dys...
Source: Comprehensive Physiology - Category: Physiology Tags: Compr Physiol Source Type: research
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