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Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD+-SIRT3 pathway

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 μM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+ levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+ precursor Niacin (50 μM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+ consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM.

Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD+-SIRT3 axis.

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Fig. 1: Macrod1 expression declines in diabetic cardiomyopathy in vivo and in vitro.
Fig. 2: Macrod1 knockout facilitates cardiac remodeling and dysfunction in DCM.
Fig. 3: Macrod1 knockout facilitates cardiac remodeling and dysfunction in DCM.
Fig. 4: Macrod1 knockout promotes myocardial oxidative stress and energy deficiency in DCM.
Fig. 5: Cardiac-specific Macrod1 overexpression alleviates cardiac remodeling and dysfunction in DCM.
Fig. 6: Cardiac-specific Macrod1 overexpression ameliorates oxidative stress in DCM.
Fig. 7: Cardiomyocyte Macrod1 overexpression alleviates PA-induced oxidative stress damage.
Fig. 8: Macrod1 improves oxidative stress by regulating the PARP1-NAD+-SIRT3 pathway.

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Acknowledgements

This work was supported by the Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20269) and the National Key R&D Program of China (2018YFC1311300).

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  1. These authors contributed equally: Yu-ting Liu, Hong-liang Qiu.

Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yu-ting Liu, Hong-liang Qiu, Hong-xia Xia, Yi-zhou Feng, Jiang-yang Deng, Yuan Yuan, Da Ke, Heng Zhou, Yan Che & Qi-zhu Tang

  2. Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China

    Yu-ting Liu, Hong-liang Qiu, Hong-xia Xia, Yi-zhou Feng, Jiang-yang Deng, Yuan Yuan, Da Ke, Heng Zhou, Yan Che & Qi-zhu Tang

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Contributions

QZT, YC, YTL, and HLQ contributed to the design and conception of the study. QZT was responsible for the financial support. YTL and HLQ designed and implemented the majority of the experiments, analyzed the majority of the data and prepared graphs and tables. YTL, HLQ, and YC wrote and edited the manuscript. HXX, YZF, JYD, YY, DK and HZ assisted with some experiments and discussed the results. All authors approved the final version.

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Correspondence to Yan Che or Qi-zhu Tang.

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Liu, Yt., Qiu, Hl., Xia, Hx. et al. Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD+-SIRT3 pathway. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01247-2

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