Preprint
The mitochondrial regulation of smooth muscle cell proliferation in type 2 diabetes
bioRxiv
Cold Spring Harbor Laboratory Press
02/16/2023
DOI: 10.1101/2023.02.15.528765
PMCID: PMC9948984
PMID: 36824758
Abstract
Background: Type 2 diabetes (T2D) is associated with a strongly increased risk for restenosis after angioplasty driven by proliferation of vascular smooth muscle cells (VSMCs). Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on ROS and intracellular [Ca2+] that both drive cell proliferation, occur in T2D and are regulated by mitochondrial activity. Methods: Using a diet-induced mouse model of T2D, the inhibition of the mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII), a regulator of Ca2+ entry via the mitochondrial Ca2+ uniporter selectively in VSMCs, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. Results: In T2D, the inhibition of mtCaMKII reduced both neointima formation after mechanical injury and the proliferation of cultured VSMCs. VSMCs from T2D mice displayed accelerated proliferation, reduced mitochondrial Ca2+ entry and membrane potential with elevated baseline [Ca2+]cyto compared to cells from normoglycemic mice. Accelerated proliferation after PDGF treatment was driven by activation of Erk1/2 and its upstream regulators. Hyperactivation of Erk1/2 was Ca2+-dependent rather than mitochondrial ROS-driven Ca2+-dependent and included the activation of CaMKII in the cytosol. The inhibition of mtCaMKII exaggerated the Ca2+ imbalance by lowering mitochondrial Ca2+ entry and increasing baseline [Ca2+]cyto, further enhancing baseline Erk1/2 activation. With inhibition of mtCaMKII, PDGF treatment had no additional effect on cell proliferation. Inhibition of activated CaMKII in the cytosol decreased excessive Erk1/2 activation and reduced VSMC proliferation. Conclusions: Collectively, our results provide evidence for the molecular mechanisms of enhanced VSMC proliferation after mechanical injury by mitochondrial Ca2+ entry in T2D. Competing Interest Statement The authors have declared no competing interest.
Details
- Title: Subtitle
- The mitochondrial regulation of smooth muscle cell proliferation in type 2 diabetes
- Creators
- Olha Koval - University of IowaEmily Nguyen - University of California San DiegoDylan Mittauer - Washington University in St. LouisKarima Ait-Aissa - University of IowaWilliam Chinchankar - University of IowaLan Qian - University of IowaMuniswamy Madesh - The University of Texas Health Science Center at San AntonioDao-Fu Dai - University of IowaIsabella Grumbach - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.1101/2023.02.15.528765
- PMID
- 36824758
- PMCID
- PMC9948984
- Publisher
- Cold Spring Harbor Laboratory Press; Cold Spring Harbor
- Language
- English
- Date posted
- 02/16/2023
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984370972202771
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