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A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure
Published on: April 30, 2020
Atrophic remodeling of the heart during vitamin D deficiency and insufficiency in a rat model
Athira Anilkumar Sudharma1, Sivaramakrishna Siginam1, Gulam M Husain2
1Department of Endocrinology, National Institute of Nutrition, Hyderabad, Telangana, India.
Abstract:
Vitamin D deficiency (VDD) is associated with skeletal muscle wasting and impaired cardiac function in humans and animals. However, the molecular events that cause cardiac dysfunction in VDD are poorly understood, and therefore, therapeutic approaches are limited. In the present study, we investigated the effects of VDD on heart function with an emphasis on signaling pathways that regulate anabolism/catabolism in cardiac muscle. Vitamin D insufficiency and deficiency led to cardiac arrhythmia, a decrease in heart weight, and an increase in apoptosis and interstitial fibrosis. Ex-vivo cultures of atria revealed an increase in total protein degradation and a decrease in de-novo protein synthesis. The catalytic activities of the major proteolytic systems: ubiquitin-proteasome system, autophagy-lysosome, and calpains were upregulated in the heart of VDD and insufficient rats. In contrast, the mTOR pathway that regulates protein synthesis was suppressed. These catabolic events were exacerbated by a decrease in the expression of myosin heavy chain and troponin genes, as well as decreased expression and activities of metabolic enzymes. These latter changes occurred despite the activation of the energy sensor, AMPK. Our results provide, compelling evidence for cardiac atrophy in Vitamin D deficient rats. Unlike the skeletal muscle, the heart responded to VDD by activating all three proteolytic systems.
Insights
Vitamin D deficiency (VDD) causes heart problems by increasing protein breakdown and decreasing protein synthesis in cardiac muscle. This leads to cardiac atrophy, impacting heart function and structure.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Vitamin D deficiency (VDD) is linked to impaired cardiac function, but the underlying molecular mechanisms remain unclear.
- Understanding these mechanisms is crucial for developing targeted therapies for VDD-related heart conditions.
Purpose of the Study:
- To investigate the impact of VDD on heart function.
- To elucidate the signaling pathways regulating anabolism and catabolism in cardiac muscle during VDD.
Main Methods:
- Assessment of cardiac function, including arrhythmia, heart weight, apoptosis, and fibrosis in VDD rats.
- Ex-vivo atrial cultures to analyze protein synthesis and degradation.
- Measurement of proteolytic system activities (ubiquitin-proteasome, autophagy-lysosome, calpains) and mTOR pathway signaling.
- Gene expression analysis of cardiac-specific proteins and metabolic enzymes.
Main Results:
- VDD induced cardiac arrhythmia, reduced heart weight, and increased apoptosis and fibrosis.
- Ex-vivo studies showed increased protein degradation and decreased protein synthesis in VDD atria.
- All major proteolytic systems were upregulated, while the mTOR pathway was suppressed in VDD hearts.
- Decreased expression of myosin heavy chain and troponin, alongside reduced metabolic enzyme activity, was observed despite AMPK activation.
Conclusions:
- VDD leads to significant cardiac atrophy in rats, characterized by increased catabolism and suppressed anabolism.
- The heart's response to VDD involves the activation of all three major proteolytic systems, unlike skeletal muscle.
- These findings highlight the detrimental effects of VDD on cardiac molecular pathways and provide a basis for future therapeutic strategies.
