bims-hafaim 2023-09-24 papers

Issue of 2023–09–24
three papers selected by
Kyle McCommis, Saint Louis University

Elife. 2023 Sep 20. pii: e85571. [Epub ahead of print]12

SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury.

Xiaoyan Yang, Hsiang-Chun Chang, Yuki Tatekoshi, Amir Mahmoodzadeh, Maryam Balibegloo, Zeinab Najafi, Rongxue Wu, Chunlei Chen, Tatsuya Sato, Jason Solomon Shapiro, Hossein Ardehali.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

Keywords: medicine; mouse

DOI: https://doi.org/10.7554/eLife.85571

PLoS One. 2023 ;18(9): e0292015

Modulation of cardiac cAMP signaling by AMPK and its adjustments in pressure overload-induced myocardial dysfunction in rat and mouse.

Anne Garnier, Jérôme Leroy, Claudine Deloménie, Philippe Mateo, Benoit Viollet, Vladimir Veksler, Mathias Mericskay, Renée Ventura-Clapier, Jérôme Piquereau.

The beta-adrenergic system is a potent stimulus for enhancing cardiac output that may become deleterious when energy metabolism is compromised as in heart failure. We thus examined whether the AMP-activated protein kinase (AMPK) that is activated in response to energy depletion may control the beta-adrenergic pathway. We studied the cardiac response to beta-adrenergic stimulation of AMPKα2-/- mice or to pharmacological AMPK activation on contractile function, calcium current, cAMP content and expression of adenylyl cyclase 5 (AC5), a rate limiting step of the beta-adrenergic pathway. In AMPKα2-/- mice the expression of AC5 (+50%), the dose response curve of left ventricular developed pressure to isoprenaline (p<0.001) or the response to forskolin, an activator of AC (+25%), were significantly increased compared to WT heart. Similarly, the response of L-type calcium current to 3-isobutyl-l-methylxanthine (IBMX), a phosphodiesterase inhibitor was significantly higher in KO (+98%, p<0.01) than WT (+57%) isolated cardiomyocytes. Conversely, pharmacological activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) induced a 45% decrease in AC5 expression (p<0.001) and a 40% decrease of cAMP content (P<0.001) as measured by fluorescence resonance energy transfer (FRET) compared to unstimulated rat cardiomyocytes. Finally, in experimental pressure overload-induced cardiac dysfunction, AMPK activation was associated with a decreased expression of AC5 that was blunted in AMPKα2-/- mice. The results show that AMPK activation down-regulates AC5 expression and blunts the beta-adrenergic cascade. This crosstalk between AMPK and beta-adrenergic pathways may participate in a compensatory energy sparing mechanism in dysfunctional myocardium.

DOI: https://doi.org/10.1371/journal.pone.0292015

J Clin Endocrinol Metab. 2023 Sep 21. pii: dgad561. [Epub ahead of print]

Association of Circulating Very Long Chain Saturated Fatty Acids with Cardiovascular Mortality in NHANES 2015-2016.

Xinmiao Tao, Lin Liu, Pingnan Ma, Jinxia Hu, Zhu Ming, Keke Dang, Yuntao Zhang, Ying Li.

BACKGROUND: Limited studies have shown a protective effect of very long chain saturated fatty acids （VLSFAs） on healthy aging, diabetes, heart failure and risk factors related to cardiovascular disease (CVD), but the role of VLSFAs on mortality risk is unclear. We aimed to investigate the association of serum docosanoic acid (C22:0) and serum lignoceric acid (C24:0) with all-cause and disease-specific mortality and to confirm the effect of VLSFAs on mortality risk in the whole, hyperlipidemia and hypertensive populations.
METHODS: A total of 4132 individuals from the 2015-2016 National Health and Nutrition Examination Survey (NHANES) were included in this study. There were 1326 and 1456 participants in the hyperlipidemia and hypertensive population, respectively. Mortality information was confirmed using the National Death Index (NDI). Multiple model calibration was performed using COX regression analysis for known risk factors to explore the association between circulating VLSFAs and all-cause or CVD or coronary heart disease (CHD) mortality.
RESULTS: In the whole population, individuals with higher circulating C22:0 and C24:0 as a percentage of total serum fatty acid levels reduced the risks of mortality of all-cause (C22:0: HR = 0.409, 95%CI = 0.271-0.618; C24:0: HR = 0.430, 95%CI = 0.283-0.651), CVD (C22:0: HR = 0.286, 95%CI = 0.134-0.612; C24:0: HR = 0.233, 95%CI = 0.101-0.538) and CHD (C22:0: HR = 0.401, 95%CI = 0.187-0.913; C24:0: HR = 0.263, 95%CI = 0.082-0.846). Similar to the whole population, individuals with higher circulating C22:0 and C24:0 as a percentage of total serum fatty acid levels in the hyperlipidemia and hypertensive populations were also protective for all-cause, CHD and CVD mortality.
CONCLUSION: Our results confirm the protective effect of high levels of circulating VLSFAs (C22:0 and C24:0) on CVD, CHD and all-cause of death in the whole, hyperlipidemia and hypertensive populations.

Keywords: All-cause Mortality; Cardiovascular Mortality; Coronary Heart Mortality; Hyperlipidemia Population; Hypertensive Population; Very Long Chain Saturated Fatty Acids

DOI: https://doi.org/10.1210/clinem/dgad561