Sirtuin 3 Deficiency Is Associated with Inhibited Mitochondrial Function and Pulmonary Arterial Hypertension in Rodents and Humans

Abstract

Suppression of mitochondrial function promoting proliferation and apoptosis suppression has been described in the pulmonary arteries and extrapulmonary tissues in pulmonary arterial hypertension (PAH), but the cause of this metabolic remodeling is unknown. Mice lacking sirtuin 3 (SIRT3), a mitochondrial deacetylase, have increased acetylation and inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial function. Sirt3KO mice develop spontaneous PAH, exhibiting previously described molecular features of PAH pulmonary artery smooth muscle cells (PASMC). In human PAH PASMC and rats with PAH, SIRT3 is downregulated, and its normalization with adenovirus gene therapy reverses the disease phenotype. A loss-of-function SIRT3 polymorphism, linked to metabolic syndrome, is associated with PAH in an unbiased cohort of 162 patients and controls. If confirmed in large patient cohorts, these findings may facilitate biomarker and therapeutic discovery programs in PAH.

The Iron Paradigm of Pulmonary Arterial Hypertension

“…These pathways range from activation of proproliferative transcription factors, such as hypoxia-inducible factor 1α, signal transducer and activator of transcription 3 and nuclear factor of activated T cells to induced epigenetic modifications, including microRNA aberrant expression, 10 methylation resulting in decreased expression of mitochondrial enzymes, such as manganese superoxide dismutase 11 or single-nucleotide polymorphisms to sirtuin-3. 12 Although a primary mitochondrial suppression in PASMCs has provided strong evidence for how many of these seemingly unrelated pathways may converge into 1 central metabolic pathway, 4,5 it still remains unclear which primary signals result in inhibition of mitochondrial or metabolic proteins in PAH. Intriguingly, many of the complexes, dehydrogenases, reductases, hydroxylases, and demethylases important for mitochondrial or metabolic function are iron-dependent.…”

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

“…SIRT3 gene-removed mice have been reported to develop an accelerated agerelated weakening in cardiac contractile function, which is characterized as an increase in end-diastolic volume, and are more prone to transaortic constriction-induced left ventricular hypertrophy [68,88]. SIRT3 gene-removed mice can also display spontaneous pulmonary hypertension and have reduced oxygen consumption rate in their pulmonary artery smooth muscle cells [89]. In those knockout cells, the investigators pointed out that the expression of HIF1α, STAT3, and NFATc2 transcription factors increased, which might be responsible for the development of this disease [89].…”

“…SIRT3 gene-removed mice can also display spontaneous pulmonary hypertension and have reduced oxygen consumption rate in their pulmonary artery smooth muscle cells [89]. In those knockout cells, the investigators pointed out that the expression of HIF1α, STAT3, and NFATc2 transcription factors increased, which might be responsible for the development of this disease [89]. Knockdown of SIRT3 expression increases the vulnerability of both H9c2 cardiomyocytes and Langendorff preparations to simulate IR injury [18].…”

Animal Models of Systemic Sclerosis

“…Mice that lack or have reduced expression of SIRT3 also develop pulmonary arterial hypertension. Nevertheless, malfunction of SIRT3 is not accompanied by the presence of inflammatory infiltrates, even though mitochondrial damage and the presence of oxidative stress have been detected [30]. Studies on SIRT3 also showed that increased expression of SIRT3 prevents the development of experimentally induced organ fibrosis and promotes the essential role of SIRT3 in maintaining cellular homeostasis of tissues during aging [29,31].…”