Dissertation
Clinical analysis of serum carnosinase in cardiometabolic disease and evaluation of novel carnosine analogs for therapeutic potential
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007333
Abstract
Cardiometabolic disease (CMD) is a health concern that affects a large population world-wide. The main attribution to CMD development is the increase of reactive oxygen (ROS) and carbonyl species (RCS) in the human body, which is often associated with mitochondria dysfunction. Mitochondria are the powerhouses for cells; however, they are also the main producers of ROS and cause RCS build up. Hence, developing therapeutic compounds capable of restoring normal mitochondria function by reducing ROS and RCS are vital in CMD treatment. Carnosine is an endogenous compound that scavenges ROS and RCS. However, it is randomly distributed in cells and is often undetectable in the blood due to serum carnosinase. Carnosine’s therapeutic potential in humans is substantially limited by carnosinase, an enzyme that hydrolyzes the peptide bond and renders carnosine unable to effectively bind with ROS nor RCS and facilitate their elimination. There are many studies that have tied serum carnosinase levels with the progression of diabetes and its complications, but no studies have investigated the association of carnosinase with heart failure. For these reasons, the first study objective was to identify any links that exist between serum carnosinase and HF. The second study objective was to develop novel mitochondria-targeted L-carnosine analogs that are safe for humans, hold similar RCS quenching ability, target mitochondria, and can evade carnosinase’s deactivation.
In this dissertation, I measured the carnosine degradation rate and serum carnosinase concentration in 140 plasma samples of left ventricular dysfunction patients who underwent heart surgery. Univariable analysis suggested that there was no association between carnosine degradation rate and carnosinase concentration. In addition, carnosine degradation rate presented a bimodal distribution which was not observed in the carnosinase protein concentration data. Multivariable analysis revealed that potential predictors to higher carnosine degradation rate were higher EF, no diabetes, and male sex. The findings to the first objective provided a first glance at the potential associations of carnosinase degradation rate with different parameters in the heart failure and/or diabetes mellitus population.
Triphenylphosphonium (TPP+) is a commonly used carrier designed for targeting mitochondria. In collaboration with Dr. Kerns (medicinal chemist at UI-College of Pharmacy), we were able to synthesize two novel carnosine analogs: TPP+-carnosine and CF3 TPP+-carnosine. In this paper, I established data that presents evidence on their RCS scavenging abilities (Aim 1. Kinetic experiment), and TPP+-carnosine’s resistance against carnosinase (Aim 2. Stability in human serum), and its efficacy in reducing oxidative stress in cardiomyocytes (Aim 3. Cell models).
For the paper’s second objective, I found that both TPP+-carnosine and CF3 TPP+-carnosine were effective at RCS binding (Aim1). TPP+-carnosine also presented resistance to carnosinase hydrolysis in human serum and should be better at ameliorating RCS accumulation in the mitochondria (Aim 2). Lastly, TPP+-carnosine protected the mitochondria in the cell studies from oxidative stress challenged by H2O2 and maintained the mitochondria’s membrane potential in primary mouse cardiomyocytes (Aim 3). Collectively, these findings support the further development and optimization of mitochondrial-targeted carnosine analogs as therapy for CMD. Future experiments will incorporate animal studies to establish the safety and efficacy profile of the novel carnosine analogs.
Details
- Title: Subtitle
- Clinical analysis of serum carnosinase in cardiometabolic disease and evaluation of novel carnosine analogs for therapeutic potential
- Creators
- I-Chau (Emily) Liang
- Contributors
- Ethan Anderson (Advisor)Guohua An (Committee Member)Jonathan Doorn (Committee Member)Michael Duffel (Committee Member)Robert Kerns (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007333
- Publisher
- University of Iowa
- Number of pages
- xiv, 79 pages
- Copyright
- Copyright 2024 I-Chau (Emily) Liang
- Language
- English
- Date submitted
- 04/22/2024
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (page 63-66).
- Public Abstract (ETD)
The main goals of this research project were to identify the association of carnosinase with heart failure, and to establish drug profiles for mitochondria-targeted carnosine analogs that can alleviate the damage that commonly occurs in cardiometabolic diseases, such as diabetes and heart diseases. High sugar and lipid conditions or diet and different disease states can lead to an increase in oxidative stress byproducts, such as reactive oxygen species or free radicals, which are harmful to the human body. The byproducts of oxidative stress are the culprits to DNA damage, inflammation, cancer, aging, and cell death. Carnosine is a dipeptide that occurs naturally in the human body. It can help in reducing oxidative stress by binding with the byproducts that are harmful so they will not cause detrimental effects to the body. However, the human body has carnosinase, which is an enzyme that breaks down carnosine and renders it unable to protect against oxidative stress. If we can synthesize a compound derived from carnosine that can avoid carnosinase and have it target the mitochondria, which is the place where most free radicals are generated, it will be very helpful especially in patients who have heart diseases and/or diabetes.
Our research on mitochondria-targeted carnosine analogs will pave roads and open paths for other researchers who are also considering developing carnosine analogs as therapeutic supplements for patients who have cardiometabolic disease or conditions such as high blood sugar or lipid levels. There is also great promise in the use of mitochondria-targeted L-carnosine analog as a supplement that is given before heart surgery to improve recovery, or a conjunctive therapy to reduce heart and liver injury in patients with diabetes or other diseases.
- Academic Unit
- Pharmacy
- Record Identifier
- 9984647355202771
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