Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes

Olha Koval; Emily Nguyen; Dylan Mittauer; Karima Ait-Aissa; William Chinchankar; Isabella Grumbach

doi:10.3390/ijms241612897

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Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes

Journal article

Open access

Peer reviewed

Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes

Olha Koval, Emily Nguyen, Dylan Mittauer, Karima Ait-Aissa, William Chinchankar and Isabella Grumbach

International journal of molecular sciences, Vol.24(16), 12897

08/15/2023

DOI: 10.3390/ijms241612897

PMCID: PMC10454141

PMID: 37629079

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Abstract

Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process.

Cardiovascular Disease

Cell Growth

Diabetes

Growth Factors

Peptides

Phosphorylation

Endoplasmic reticulum

Kinases

Mitochondria

Proteins

Smooth muscle

Details

Title: Subtitle: Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes
Creators: Olha Koval - University of Iowa
Emily Nguyen - University of Iowa
Dylan Mittauer - University of Iowa
Karima Ait-Aissa - University of Iowa
William Chinchankar - University of Iowa
Isabella Grumbach - University of Iowa
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.24(16), 12897
DOI: 10.3390/ijms241612897
PMID: 37629079
PMCID: PMC10454141
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Publisher: MDPI AG
Grant note: DOI: 10.13039/100000002, name: NIH, award: R01 HL108932, R01 HL157956, F30 HL131078-01, T32 GM007337; DOI: 10.13039/501100000938, name: Veterans Affairs Iowa City, award: I01 BX000163; DOI: 10.13039/100000968, name: American Heart Association, award: 17GRNT33660032
Language: English
Date published: 08/15/2023
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Internal Medicine
Record Identifier: 9984455982802771

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