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The Worsening of Myocardial Ischemia–Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology

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Abstract

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request

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Acknowledgements

The authors would like to thank the Indian council of medical research (3/1/2(22)/Env/2021-NCD-II) and Department of science and technology (CRG/2021/000227) for funding this research.

Funding

Bhavana Sivakumar was funded by Indian council of medical research (ICMR), no: 3/1/2(22)/Env/2021-NCD-II as part of the senior research fellow (SRF) fellowship. Dr Gino A Kurian was supported by Department of Science and technology, India through grant-in-aid (CRG/2021/000227).

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Authors and Affiliations

  1. Vascular Biology Lab, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, Tamil Nadu, India

    Bhavana Sivakumar & Gino A. Kurian

  2. School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, 613401, Tamil Nadu, India

    Gino A. Kurian

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  1. Bhavana Sivakumar
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BS conducted the experiments, wrote the main manuscript, prepared the figures, and then reviewed and corrected the manuscript. GAK edited and reviewed the manuscript file. All authors reviewed the manuscript.

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Correspondence to Gino A. Kurian.

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Sivakumar, B., Kurian, G.A. The Worsening of Myocardial Ischemia–Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology. Cardiovasc Toxicol 24, 1236–1252 (2024). https://doi.org/10.1007/s12012-024-09920-y

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