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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
MiR-203 improves cardiac dysfunction by targeting PARP1-NAD+ axis in aging murine
Limin Zhao1, Pingping Tang1, Yuan Lin1
1Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Insights
MicroRNA-203 (miR-203) levels decrease with age, contributing to heart aging. Restoring miR-203 protects against heart aging by maintaining NAD+ homeostasis and preventing senescence.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Aging Research
Background:
- Heart aging is a major risk factor for cardiovascular diseases in the elderly.
- Nicotinamide adenine dinucleotide (NAD+) depletion is a key feature of cardiac aging, but its regulatory mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of microRNA-203 (miR-203) in age-related cardiac dysfunction and NAD+ homeostasis.
- To explore miR-203 as a potential therapeutic target for combating heart aging.
Main Methods:
- Correlation analysis of blood miR-203 levels with human age.
- Assessment of miR-203 expression in aged mouse hearts and senescent cardiomyocytes.
- Generation of transgenic mice overexpressing miR-203 (TgN (miR-203)).
- In vitro studies using D-galactose-induced senescent cardiomyocytes with miR-203 overexpression or knockdown.
- Mechanistic investigation of miR-203 targeting of PARP1 (Poly (ADP-ribose) polymerase 1).
Main Results:
- Blood miR-203 levels negatively correlate with human age.
- miR-203 expression is significantly reduced in aged mouse hearts and senescent cardiomyocytes.
- Overexpression of miR-203 in transgenic mice conferred resistance to aging-induced cardiac dysfunction, remodeling, and senescence.
- miR-203 overexpression protected cardiomyocytes from senescence and mitochondrial damage, while knockdown exacerbated these effects.
- miR-203 directly inhibits PARP1 expression, thereby reducing NAD+ depletion and improving mitochondrial function.
Conclusions:
- miR-203 is identified as a senescence-associated microRNA that plays a crucial role in regulating cardiac NAD+ homeostasis and preventing heart aging.
- Restoring miR-203 levels can counteract age-related cardiac decline by inhibiting PARP1, preserving NAD+ levels, and enhancing mitochondrial function.
- miR-203 represents a novel genetic tool for anti-heart aging strategies.
Abstract:
Heart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA-203 (miR-203) as a senescence-associated microRNA that regulates NAD+ homeostasis. We found that the blood miR-203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR-203 (TgN (miR-203)) showed resistance to aging-induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR-203 significantly prevented D-gal-induced cardiomyocyte senescence and mitochondrial damage, while miR-203 knockdown aggravated these effects. Mechanistically, miR-203 inhibited PARP1 expression by targeting its 3'UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR-203 as a genetic tool for anti-heart aging by restoring NAD+ function in cardiomyocytes.
