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Published on: February 25, 2014
Adjusted vascular contractility relies on integrity of progranulin pathway: Insights into mitochondrial function
Shubhnita Singh1,2,3,4, Ariane Bruder-Nascimento1,2,3, Rafael M Costa1,2,3,5
1Department of Pediatrics at UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
Insights
Progranulin (PGRN) preserves vascular contractility by regulating mitochondrial function and mitophagy. Loss of PGRN is a risk factor for cardiovascular disease (CVD), highlighting its importance in vascular health.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Molecular Genetics
Background:
- Cardiovascular disease (CVD) is a leading global cause of mortality, with vascular contractility and mitochondrial function being critical pathogenic factors.
- Progranulin (PGRN), encoded by the progranulin gene (GRN), is known for its anti-inflammatory properties, but its role in CVD is unclear.
Conclusions:
- PGRN is crucial for maintaining vascular contractility through regulation of mitophagy, mitochondrial complex I activity, and redox signaling.
- Loss of PGRN function is identified as a significant risk factor in the development of cardiovascular disease.
Objective:
Cardiovascular disease (CVD) is a global health crisis and a leading cause of mortality. The intricate interplay between vascular contractility and mitochondrial function is central to CVD pathogenesis. The progranulin gene (GRN) encodes glycoprotein progranulin (PGRN), a ubiquitous molecule with known anti-inflammatory property. However, the role of PGRN in CVD remains enigmatic. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality.
Method:
Our investigation utilized aortae from male and female C57BL6/J wild-type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) mice, encompassing wire myograph assays to assess vascular contractility and primary aortic vascular smooth muscle cells (VSMCs) for mechanistic insights.
Results:
Our results showed suppression of contractile activity in PGRN-/- VSMCs and aorta, followed by reduced α-smooth muscle actin expression. Mechanistically, PGRN deficiency impaired mitochondrial oxygen consumption rate (OCR), complex I activity, mitochondrial turnover, and mitochondrial redox signaling, while restoration of PGRN levels in aortae from PGRN-/- mice via lentivirus delivery ameliorated contractility and boosted OCR. In addition, VSMC overexpressing PGRN displayed higher mitochondrial respiration and complex I activity accompanied by cellular hypercontractility. Furthermore, increased PGRN triggered lysosome biogenesis by regulating transcription factor EB and accelerated mitophagy flux in VSMC, while treatment with spermidine, an autophagy inducer, improved mitochondrial phenotype and enhanced vascular contractility. Finally, angiotensin II failed to induce vascular contractility in PGRN-/- suggesting a key role of PGRN to maintain the vascular tone.
Conclusion:
Our findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial complex I activity, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in CVD development.
