The sirtuin 3 (SIRT3) enzyme may prevent the development of cardiovascular diseases such as pulmonary arterial hypertension (PAH) by protecting the mitochondria, according to a new review published in Free Radical Biology and Medicine.

Therefore, sirtuin 3 agonists may serve as potential treatments for cardiovascular diseases, the authors said. SIRT3 is a deacetylase that regulates mitochondrial protein acetylation and thus plays a role in metabolism, redox balance, and mitochondrial dynamics. This way, it protects mitochondria from damage.

Defects in SIRT3 lead to the development of various cardiovascular diseases including PAH, which is characterized by the narrowing and thickening of the pulmonary arteries causing increased resistance to blood flow and right ventricular failure in the long run.

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A good understanding of how SIRT3 works and its role in cardiovascular disease is of great importance to be able to develop new therapeutic approaches. In this review, researchers report the various functions of the enzyme in mitochondrial function and cardiovascular diseases. 

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One of these functions is to regulate fatty acid and glucose metabolism and participate in the tricarboxylic acid, electron transport chain, and ATP synthesis. This way, SIRT3 helps maximize mitochondrial oxygen usage and reduces reactive oxygen species (ROS) production. 

SIRT3 also activates the mitochondrial antioxidant system thereby eliminating the generated ROS. In case of mitochondrial damage, SIRT3 induces autophagy and eliminates damaged mitochondria.

In the case of PAH, research in animal models has shown that mice lacking SIRT3 develop spontaneous PAH and right heart failure. Moreover, patients with PAH have decreased SIRT3 activity. These data suggest that increasing SIRT3 activity may serve as therapy for PAH.

For example, the sirtuin agonist resveratrol may preserve mitochondrial function and improve PAH by activating SIRT3, the authors said. Similarly, metformin, the first-line therapy for type 2 diabetes can activate the SIRT3-AMPK signaling pathway and help resist PAH-induced right heart failure.

A better understanding of the function of SIRT3 can facilitate the development of new therapies for PAH and other cardiovascular diseases, they concluded.


Cao M, Zhao Q, Sun X, et al. Sirtuin 3: emerging therapeutic target for cardiovascular diseases. Free Radic Biol Med. 2022;180(11):63-74. doi:10.1016/j.freeradbiomed.2022.01.005