Conventionally, oxidative stress is considered pathological to cardiac protein quality control (PQC), which rationalizes the therapeutic potential of antioxidants. However, many clinical trials of antioxidant supplementation failed to deliver a positive impact and, rather, demonstrated adverse effects in various organs, including those in the cardiovascular system. Emerging evidence suggests that reductive stress (RS), also known as antioxidative stress, may cause ER stress and accumulation of mis/unfolded proteins. To fully comprehend the molecular interplay underlying RS-mediated proteotoxicity and the time frame for myocardium experiencing a transition from adaptive to maladaptive remodeling, it is critical to identify the molecular participants, their dynamic interplay, and resulting sequential events (e.g., autophagy) that regulate PQC. Recently, our exciting and novel clinical observations revealed a link of chronic RS (cRS) underlying disease progression of human heart failure (HF). We screened a selected group of HF patients (n=50, without other major comorbidities) for their peripheral blood redox state; among them, a subset (n=8) displayed the RS condition. Our proposed study will entail a translational component utilizing proteomics approaches and molecular biology to better understand the etiology of RS in mouse models and to identify its relevance in HF patients. Our central hypothesis is that cRS will alter proteome properties (e.g., protein dynamics & post- translational modifications, or PTMs) and damage autophagy signaling, leading to persistent proteotoxicity and cardiac dysfunction, thereby driving maladaptive remodeling in animal models and in human heart diseases. We propose three aims:
Aim 1 will determine altered protein dynamics, redistributed PTMs, and perturbed autophagy subproteome in RS conditions. We will define the ?reductome signatures? in control and cRS phenotypes.
Aim 2 will examine the impact of cRS on progressive damage of autophagy that may lead to insufficient cargo-clearance and proteotoxicity in the myocardium over time. We will assess autophagosome formation, autophagy flux, and protein folding capacity under cRS conditions and examine whether enhancing autophagy delays and/or prevents proteotoxicity in mice.
Aim 3 will examine the ?redox phenotype? in the peripheral blood of HF patients using HPLC based quantification of (a) GSH redox ratio, (b) lipid peroxidation, and (c) total antioxidant capacity, as well as extract the molecular ?reductome signatures? in HF patients with RS using a computational platform to determine essential proteome features and regulatory pathways.
This aim will establish a translational value for the RS hypothesis in human HF. We have assembled a multidisciplinary team (scientists & physicians) with documented expertise in redox biology, biochemistry, proteomics, and computational analyses. The genetic mouse models of RS, the technology platforms, and the biochemical assays to evaluate RS in mouse and in human are all established in our laboratories. We anticipate the successful completion of our proposed goals.
Accumulation and aggregation of defective proteins in the heart impair protein quality control and induce cardiac hypertrophy, leading to heart failure. Reductive stress (abnormal increase in antioxidants) leads to unresolved ER stress, sustained accumulation of mis/unfolded proteins, and augmented proteotoxicity. In this project, we will use newly developed animal models with heart-specific RS to identify molecular signatures and genetic mutations relevant to autophagy-driven protein quality control that will propel personalized therapeutic strategies for heart failure patients based on their redox state.
|Brewer, Rachel A; Collins, Helen E; Berry, Ryan D et al. (2018) Temporal partitioning of adaptive responses of the murine heart to fasting. Life Sci 197:30-39|
|Bolus, Daniel J; Shanmugam, Gobinath; Narasimhan, Madhusudhanan et al. (2018) Recurrent heat shock impairs the proliferation and differentiation of C2C12 myoblasts. Cell Stress Chaperones 23:399-410|
|Quiles, Justin M; Narasimhan, Madhusudhanan; Shanmugam, Gobinath et al. (2017) Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice. BMC Genomics 18:509|
|Shanmugam, Gobinath; Narasimhan, Madhusudhanan; Conley, Robbie L et al. (2017) Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling. Front Physiol 8:268|
|McGinnis, Graham R; Tang, Yawen; Brewer, Rachel A et al. (2017) Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart. J Mol Cell Cardiol 110:80-95|
|Shanmugam, Gobinath; Narasimhan, Madhusudhanan; Tamowski, Susan et al. (2017) Constitutive activation of Nrf2 induces a stable reductive state in the mouse myocardium. Redox Biol 12:937-945|
|Narasimhan, Madhusudhanan; Rajasekaran, Namakkal-Soorappan (2017) Cardiac Aging - Benefits of Exercise, Nrf2 Activation and Antioxidant Signaling. Adv Exp Med Biol 999:231-255|
|Quiles, Justin M; Narasimhan, Madhusudhanan; Mosbruger, Timothy et al. (2017) Identification of transcriptome signature for myocardial reductive stress. Redox Biol 13:568-580|
|Narasimhan, Madhusudhanan; Rajasekaran, Namakkal S (2016) Exercise, Nrf2 and Antioxidant Signaling in Cardiac Aging. Front Physiol 7:241|
|Kumar, Radhakrishnan Rajesh; Narasimhan, Madhusudhanan; Shanmugam, Gobinath et al. (2016) Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress. J Transl Med 14:86|
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