Paras Kumar Mishra, PhD
Associate Professor at University of Nebraska Medical Center
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Paras Kumar Mishra, PhD
Associate Professor at University of Nebraska Medical Center
Welcome to the Mishra Lab
Understanding How Diabetes Remodels the Heart — and How We Can Protect It
The Mishra Lab studies how diabetes and metabolic stress damage the heart. Our goal is to define the molecular and cellular mechanisms that drive diabetic cardiomyopathy and diabetes-induced heart failure, and to identify new strategies to preserve cardiac structure and function.
Led by Paras Kumar Mishra, PhD, our laboratory uses a translational research approach that connects discoveries from human heart tissue, mouse models, and cell culture systems. We combine cardiac physiology, molecular biology, imaging, multi-omics technologies, and mechanistic interventions to understand how diabetes alters the heart from the molecular level to whole-organ function.
Our research focuses on key mechanisms that drive diabetic cardiac injury, including:
Lipid remodeling | Mitochondrial dysfunction | Ferroptosis | MMP9 signaling | miRNA regulation | Hydrogen sulfide biology | Exercise physiology | Structural and functional cardiac remodeling
Together, these areas help us answer one central question:
How does diabetes remodel the heart, and how can we intervene before irreversible heart failure develops?
Our Mission
The Mishra Lab studies how diabetes and metabolic stress damage the heart. Our goal is to define the molecular and cellular mechanisms that drive diabetic cardiomyopathy and diabetes-induced heart failure, and to identify new strategies to preserve cardiac structure and function.
Led by Paras Kumar Mishra, PhD, our laboratory uses a translational research approach that connects discoveries from human heart tissue, mouse models, and cell culture systems. We combine cardiac physiology, molecular biology, imaging, multi-omics technologies, and mechanistic interventions to understand how diabetes alters the heart from the molecular level to whole-organ function.
Our research focuses on key mechanisms that drive diabetic cardiac injury, including:
Lipid remodeling | Mitochondrial dysfunction | Ferroptosis | MMP9 signaling | miRNA regulation | Hydrogen sulfide biology | Exercise physiology | Structural and functional cardiac remodeling
Together, these areas help us answer one central question:
How does diabetes remodel the heart, and how can we intervene before irreversible heart failure develops?
Our Mission
Diabetes is a major risk factor for heart failure. However, diabetic heart failure is not simply heart failure occurring in a person with diabetes. It has distinct biological features, including lipid accumulation, metabolic inflexibility, mitochondrial dysfunction, oxidative stress, inflammation, fibrosis, and loss of cardiomyocytes.
The mission of the Mishra Lab is to define these mechanisms and translate them into new therapeutic opportunities for diabetic heart disease.
We aim to:
Understand how diabetes damages the myocardium
Identify molecular pathways that drive cardiac remodeling
Define mechanisms of cardiomyocyte injury and cell death
Discover therapeutic targets that preserve cardiac function
Train the next generation of cardiovascular scientists
Collaborate across disciplines to advance translational heart research
The mission of the Mishra Lab is to define these mechanisms and translate them into new therapeutic opportunities for diabetic heart disease.
We aim to:
Understand how diabetes damages the myocardium
Identify molecular pathways that drive cardiac remodeling
Define mechanisms of cardiomyocyte injury and cell death
Discover therapeutic targets that preserve cardiac function
Train the next generation of cardiovascular scientists
Collaborate across disciplines to advance translational heart research
What We Study
The Mishra Lab investigates the molecular mechanisms that make the diabetic heart vulnerable to remodeling, dysfunction, and failure.
Myocardial Cell Death: A Precursor to Heart Failure
Myocardial cell death is a major contributor to the development and progression of heart failure. In diabetes, excess lipid accumulation, mitochondrial dysfunction, oxidative stress, and metabolic imbalance activate injury pathways that weaken the heart over time.
The Mishra Lab investigates how cardiomyocytes are injured and lost in diabetes-induced heart failure, with a focus on regulated cell death mechanisms such as ferroptosis. Our work also recognizes that diabetic cardiomyopathy has distinct molecular features and may affect women disproportionately, underscoring the need for inclusive and targeted therapeutic strategies.
To advance the field, the Mishra Lab has contributed to comprehensive guidelines for evaluating cell death, providing a standardized framework for researchers studying cardiac injury and remodeling. By understanding how myocardial cell death begins and progresses, we aim to identify strategies that can slow or prevent heart failure in patients with diabetes.
The Mishra Lab investigates the molecular mechanisms that make the diabetic heart vulnerable to remodeling, dysfunction, and failure.
Myocardial Cell Death: A Precursor to Heart Failure
Myocardial cell death is a major contributor to the development and progression of heart failure. In diabetes, excess lipid accumulation, mitochondrial dysfunction, oxidative stress, and metabolic imbalance activate injury pathways that weaken the heart over time.
The Mishra Lab investigates how cardiomyocytes are injured and lost in diabetes-induced heart failure, with a focus on regulated cell death mechanisms such as ferroptosis. Our work also recognizes that diabetic cardiomyopathy has distinct molecular features and may affect women disproportionately, underscoring the need for inclusive and targeted therapeutic strategies.
To advance the field, the Mishra Lab has contributed to comprehensive guidelines for evaluating cell death, providing a standardized framework for researchers studying cardiac injury and remodeling. By understanding how myocardial cell death begins and progresses, we aim to identify strategies that can slow or prevent heart failure in patients with diabetes.
Pioneering Discoveries in Ferroptosis, Lipid Remodeling, and Heart Disease
The Mishra Lab has made important contributions to defining molecular drivers of diabetic heart failure, particularly those involving lipid-mediated injury, mitochondrial dysfunction, ferroptosis, and MMP9 signaling.
The Mishra Lab has made important contributions to defining molecular drivers of diabetic heart failure, particularly those involving lipid-mediated injury, mitochondrial dysfunction, ferroptosis, and MMP9 signaling.
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Ferroptosis in Human Heart Failure
Our work has identified ferroptosis, an iron-dependent and lipid peroxidation–driven form of cell death, as an important mechanism of myocardial injury in human heart failure. These findings highlight new opportunities to preserve cardiomyocytes and protect cardiac function. -
MMP9 Signaling and Ferroptosis
Building on this work, the lab has investigated the role of Matrix Metalloproteinase-9, or MMP9, in ferroptosis-related cardiac injury. Beyond its traditional role in extracellular matrix remodeling, MMP9 may influence intracellular stress pathways that regulate mitochondrial dysfunction, iron homeostasis, lipid peroxidation, and cardiomyocyte survival. -
Electrostatic Lipidopathy in Diabetic Heart Failure Our recent research has identified a new form of lipid remodeling in human diabetic heart failure that we call electrostatic lipidopathy. This refers to changes in the charge properties of myocardial lipids, including enrichment of negatively charged phospholipids and sphingolipids.
This lipid charge imbalance may disrupt membrane architecture, impair mitochondrial function, increase oxidative injury, and promote ferroptosis-related cardiac damage. These findings suggest that diabetic heart failure may be driven not only by lipid overload, but also by altered lipid charge architecture. - Innovation in Cardiomyocyte Gene Delivery and Mechanistic Modeling. Our lab also advances cardiovascular research by improving the experimental tools used to study disease mechanisms. We developed optimized culture and transfection protocols for H9c2 and HL-1 cardiomyocyte cell lines, comparing lipid- and polymer-based methods to improve transfection efficiency while reducing cytotoxicity. This methodological work supports more reliable, reproducible, and mechanistically precise studies of gene regulation.
Decoding the Unique Challenges of Diabetes-Induced Heart Failure
Diabetes-induced heart failure is distinct from non-diabetic heart failure due to its unique pathophysiology:
Diabetes-induced heart failure is distinct from non-diabetic heart failure due to its unique pathophysiology:
- Metabolic Remodeling: Diabetic hearts exhibit a shift from glucose to fatty acid metabolism, which increases mitochondrial stress and reduces energy efficiency.
- Lipid Remodeling, Lipotoxicity, and Gut-Heart Signaling: Gut dysbiosis may contribute to excess lipid accumulation in cardiomyocytes, promoting lipotoxic stress, mitochondrial injury, oxidative damage, and cardiac dysfunction.
- Patient-Specific Mechanisms of Diabetic Heart Failure: Diabetic heart failure is biologically distinct from non-diabetic heart failure and may differ by sex and diabetes type. Our lab studies how diabetes-specific factors - including altered glucose use, increased fatty acid reliance, ketone metabolism, lipid overload, mitochondrial stress, and reduced metabolic flexibility - make the heart less energy efficient and more vulnerable to remodeling and failure. We are particularly interested in how these mechanisms differ across diabetic vs. non-diabetic heart failure, type 1 vs. type 2 diabetes, and sex-specific risk profiles. By defining these patient-specific mechanisms, we aim to identify more precise therapeutic strategies for diabetic cardiomyopathy and diabetes-induced heart failure.
Innovative Therapeutic Strategies
Our lab is exploring novel therapies to mitigate these challenges, including:
Our lab is exploring novel therapies to mitigate these challenges, including:
- miRNA-Based Therapeutics: Cardiac lipid accumulation is a characteristic feature of diabetic heart failure and contributes to lipotoxic stress, mitochondrial dysfunction, adverse remodeling, and impaired cardiac function. Our work focuses on the cardioprotective microRNA miR-133a, which is downregulated in the diabetic heart. To define its therapeutic potential, we developed a diabetic mouse model with cardiomyocyte-specific overexpression of miR-133a. Restoration of miR-133a prevented intramyocardial lipid accumulation in diabetic hearts, suggesting that miR-133a may protect against early lipid-driven cardiac injury in prediabetes and diabetes. We have also delivered miR-133a mimics to diabetic hearts in preclinical rodent models and found that miR-133a therapy attenuates adverse cardiac remodeling, including hypertrophy and fibrosis, while improving cardiac function. Together, these studies support miR-133a–based approaches as a promising strategy to reduce lipid accumulation, limit pathological remodeling, and preserve cardiac function in diabetic heart disease.
- MMP9 Targeting: We investigate Matrix Metalloproteinase-9 (MMP9) as a regulator of diabetic cardiac remodeling, cardiomyocyte injury, and heart failure progression. Our studies have shown that MMP9 contributes to diabetes-induced contractile dysfunction, extracellular matrix remodeling, miR-133a upregulation, epigenetic and autophagy dysregulation, oxidative stress signaling, and hyperglycemia-induced cell death. More recent work expands this concept by highlighting noncanonical intracellular roles of MMP9, including regulation of antioxidant signaling through SOD3 and ferroptosis-related pathways involving mitochondrial injury, lipid peroxidation, GPX4 dysfunction, and iron imbalance. Together, these findings support MMP9 targeting as a strategy to reduce maladaptive remodeling, preserve cardiomyocyte survival, and improve cardiac function in diabetic heart disease.
- Hydrogen Sulfide Biology: Hydrogen sulfide, or H₂S, is an endogenous cardioprotective signaling molecule that helps protect against myocardial cell death, preserve mitochondrial integrity, reduce oxidative stress, and support cardiac function. Our work has shown that H₂S can ameliorate homocysteine-induced cardiac remodeling and dysfunction, highlighting its potential to counteract metabolic and oxidative stress–driven myocardial injury. Exercise training promotes cardiac H₂S biosynthesis preventing myocardial cel death in diabetic cardiomyopathy. These findings support H₂S-based approaches as a promising strategy to protect the heart from adverse remodeling and functional decline.
Join Us in Transforming Cardiac Care
The Mishra Lab is committed to advancing the understanding of diabetic heart failure, training the next generation of scientists, and translating mechanistic discoveries into therapeutic opportunities.
We welcome students, fellows, researchers, clinicians, and collaborators interested in diabetic cardiomyopathy, lipid remodeling, mitochondrial dysfunction, ferroptosis, MMP9 signaling, miRNA biology, hydrogen sulfide signaling, exercise physiology, and cardiac remodeling.
Together, we aim to define new mechanisms and develop new strategies to protect the diabetic heart.
The Mishra Lab is committed to advancing the understanding of diabetic heart failure, training the next generation of scientists, and translating mechanistic discoveries into therapeutic opportunities.
We welcome students, fellows, researchers, clinicians, and collaborators interested in diabetic cardiomyopathy, lipid remodeling, mitochondrial dysfunction, ferroptosis, MMP9 signaling, miRNA biology, hydrogen sulfide signaling, exercise physiology, and cardiac remodeling.
Together, we aim to define new mechanisms and develop new strategies to protect the diabetic heart.
Mentoring is a cornerstone of my academic mission. My graduate students have achieved significant recognition, securing several prestigious national awards. Notably, one student won 1st place in The Science Coalition’s Fund It Forward Student Video Challenge in 2019 (Video Link) , while another garnered 2nd place at Research!America’s 2020 Flash Talks Competition during the National Health Research Forum (Link: https://www.unmc.edu/news.cfm?match=26235). Additionally, my students have been awarded the NIH F31, AHA Predoctoral, AHA Postdoctoral, and UNMC Presidential Graduate Fellowships and the UNMC Program of Excellence Assistantship, underscoring the high caliber of our research training and mentorship.