Research

Research Syponosis

Maintaining redox homeostasis under basal and mild adaptations (eustress) to stress conditions is critical to preserve the physiological processes in a cell/organism. In the light of that, our laboratory is interested in the transcriptional mechanisms behind the redox extremes i.e. OXIDATIVE and REDUCTIVE STRESS. In particular, we focus on the reductive arm of the redox and how it contributes to various pathologies including cardiac remodeling/heart failure, protein aggregation, neuronal and cellular differentiation. Reductive stress is an imbalance between cellular oxidant levels and its neutralizing capacity (antioxidants), wherein there is excessive neutralizing capacity than oxidants that impedes the normal functioning of cellular machinery. Nuclear erythroid 2-related factor 2 (Nrf2) is the master transcription factor that regulates hundreds of key antioxidant enzymes. To understand these relationships under acute and chronic settings, we have been using in vitro and in vivo models (cardiomyocytes/ neuronal/myoblasts cell cultures, transgenic/knockout mouse models) bearing oxidative or reductive stress. Subsequently, we determine whether or not the SHIFT in REDOX STATE could be a causal mechanism for protein misfolding and aggregation leading to proteotoxic cardiomyopathy and neurodegenerative diseases. In addition, our lab also focuses on the impact of the redox shifts on the benefits of exercise and how it contribute to achieve a healthy aging. Our approach is interdisciplinary encompassing redox biology, biochemistry, molecular biology, bioinformatics and non-invasive ultrasound imaging procedures. From the advancements we have made thus far in the field of RS, we believe that “as much as it is necessary to study the oxidative capacity of the cell, concept of reductive power in the context of a pathology should also be viewed as a “bombardier beetle” that when disturbed can spray noxious reactive chemicals”.

Current Projects

1. Reductive Stress in Heart and Cardiac Remodeling
2. NeuRedox: Neuronal Redox Mechanisms and Reductive Stress in Alzheimer’s disease
3. Reductive Stress in Cellular Differentiation and Regeneration
4. Transcriptional Regulation of Reductive Stress
5. Benefits of exercise in regulating Nrf2 activation, and cardiac aging

1. Reductive Stress in Heart and Cardiac Remodeling

In the process of understanding how and why reductive stress occur and also important to gain insight into the long-term effect of RS, our research discovered that sustained activation of nuclear erythroid-2 like factor-2 (Nrf2), transcriptional regulator of antioxidant genes significantly contributes to RS in the transgenic mouse heart expressing human mutant CryAB (hR120GCryAB) that is associated with protein aggregation cardiomyopathy (MPAC).This study revealed the sinister consequences of overcompensation by Nrf2 in the context of cardiac remodeling and highlighted the “double-edged sword” attribute of Nrf2, i.e.- protective upon transient activation in response to stress, but injurious upon persistent activation. It is obvious that a definite degree of protein oxidation seems to be essential for key protein quality control mechanisms, echoing the eminence of redox equilibrium in cellular homeostasis. Thus clear, that any effort at influencing the redox milieu through Nrf2 for therapeutic purposes will require careful optimization in analyzing dose dependent effects to prevent destruction. RS causes pathological heart enlargement and diastolic dysfunction in a mouse model. The study used transgenic mice that had upregulated genes for antioxidants in the heart, which increased the amounts of antioxidant proteins and reduced glutathione, creating RS. We convey the message that antioxidant-based therapeutic approaches for human heart failure should consider a thorough evaluation of antioxidant levels before the treatment. Thus, a chronic consumption of antioxidant drugs by any individual without knowing their redox state might result in RS, which can induce pathology and slowly damage the heart.

2. NeuRedox: Neuronal Redox Mechanisms and Reductive Stress in Alzheimer’s disease

Disruption of redox homeostasis shifting toward oxidative stress is often associated with neurodegeneration. Recently emerging reports suggest that antioxidant-induced reductive stress has untoward consequences on brain structure and function. Our ongoing efforts are focused on defining how RS contributes to neurodegeneration and cognitive dysfunction. We also seek to define how RS promotes protein aggregation, a common manifestation in neurodegenerative diseases such as Alzheimer’s diseases. We anticipate that in the long-term, developing unifying principals for redox alterations will lead to improvements in combating neuronal diseases and human health.

3. Reductive Stress in Cellular Differentiation and Regeneration

A balance between oxidants and reductants confer a steady state of physiological signaling required for cellular differentiation, proliferation and regeneration. We believe that alteration in redox homeostasis to either extremes i.e. oxidative and reductive will impair these processes. Our approach is to fine-tune the redox through pharmacological or genetic manipulations and observe how it impacts the cellular proliferation, differentiation and regeneration.

4. Transcriptional Regulation of Reductive Stress

Cellular redox status is reflected in the balance between a number of reduced or oxidized molecular pairs including GSH/GSSG, NADPH/NADP, and NADH/NAD. The function of a number of transcription factors, as well as important DNA modifying enzymes, appears sensitive to these redox pairs, implying yet another way that cellular redox status is coupled to transcriptional outputs. In particular, our focus is on identifying the transcriptional dynamics in a reductive milieu and how it contributes to cardiac disease pathogenesis.

5. Benefits of exercise in regulating Nrf2 activation, and cardiac aging

We are one of the few labs focusing on the non-pharmacological induction of Nrf2 in cardiac aging. We have shown that acute exercise stress (AES) promoted Nrf2 signaling and the transcription of an array of cytoprotective/ antioxidant genes through ROS generation, but only induced oxidative stress in Nrf2 deficient hearts. In addition, our efforts have also provided evidence for the first time that only moderate exercise training increased the ability of aging hearts to cope with oxidative stress and Endurance Exercise Stress (EES) exacerbated deregulated Nrf2-antioxidant Mechanisms. Our continuing efforts are to investigate whether chronic regimented and spontaneous exercise (to increase adaptive response) can induce Nrf2- signaling and confer cardio-protection in the aging hearts.