Cardiac-Specific Gene Expression Facilitated by an Enhanced Myosin Light Chain Promoter

Boecker, Wolfgang; Bernecker, Oliver Y.; Wu, Joseph C.; Zhu, Xiaojuan; Sawa, Tomohiro; Grazette, Luanda; Rosenzweig, Anthony; Monte, Federica del; Schmidt, Ulrich; Hajjar, Roger J.

doi:10.1162/1535350041464847

Cited by 37 publications

(15 citation statements)

References 18 publications

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“…Accordingly, we generated a recombinant AAV9 encoding an untagged version of mouse Hrd1. Expression of Hrd1 was directed to ventricular myocytes using a previously described form of the myosin regulatory light chain 2 promoter 35, 36 , which we previously showed to support increased protein expression in >80% of mouse cardiac myocytes, in vivo 37, 38 . In the present study, 10 11 genome-containing units of AAV9-Con or AAV9-Hrd1 were administered to mice by tail vein injection.…”

Section: Resultsmentioning

confidence: 99%

Hrd1 and ER-Associated Protein Degradation, ERAD, Are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes

Doroudgar

Völkers

Thuerauf

et al. 2015

Circulation Research

103

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Rationale Hrd1 is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER protein quality control by ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER stress. Neither Hrd1 nor ERAD have been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function. Objective The objectives of this study were to elucidate roles for Hrd1 in ER stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, in vivo. Methods and Results The effects of siRNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus (AAV)-mediated Hrd1 knockdown and overexpression were examined in the hearts of mice subjected to pressure-overload induced pathological cardiac hypertrophy, which challenges protein-folding capacity. In cardiac myocytes, the ER stressors, thapsigargin (TG) and tunicamycin (TM) increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, TG and TM dramatically decreased ERAD, while increasing maladaptive ER stress proteins and cell death. In vivo, Hrd1 knockdown exacerbated cardiac dysfunction, and increased apoptosis and cardiac hypertrophy, while Hrd1 overexpression preserved cardiac function, and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure-overload. Conclusions Hrd1 and ERAD are essential components of the adaptive ER stress response in cardiac myocytes. Hrd1 contributes to preserving heart structure and function in a mouse model of pathological cardiac hypertrophy.

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Section: Resultsmentioning

confidence: 99%

Hrd1 and ER-Associated Protein Degradation, ERAD, Are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes

Doroudgar

Völkers

Thuerauf

et al. 2015

Circulation Research

103

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show abstract

“…Tissue-specific promoters can be used to restrict transgene expression to the desired target cell population and avoid unintended cells such as antigenpresenting cells. For example, cardiomyocyte-specific promoters such as alpha-myosin heavy and light chains have been employed to restrict gene expression to the myocardium (Boecker et al, 2004). Similarly, the smooth musclespecific promoter SM22a has been demonstrated to restrict gene expression to cells of this type.…”

Section: Tissue-specific Promotersmentioning

confidence: 99%

Targeting Sarcoplasmic Reticulum Calcium ATPase by Gene Therapy

Gwathmey¹,

Yerevanian²,

Hajjar³

2013

Human Gene Therapy

Self Cite

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“…For example, imaging studies on inflammatory markers such as proteases (cathepsins and MMPs), activated macrophages (expressing iron oxide), and activated endothelium (intercellular and vascular adhesion molecules) have been performed in atherosclerotic mice 19,24. Molecular imaging can probe polymorphisms of ECM gene expression in-vivo in models of cardiovascular disease,12,105 and can potentially be translated to perform real-time in-vivo characterization of scaffold matrices (either seeded or with the potential of attracting endogenous cells) implanted in animal models. Other imaging modalities such as optical coherence tomography (OCT)15,47 and intravascular ultrasound (IVUS)111 have been used to assess collagen content of coronary atherosclerotic plaque; allowing real-time in-vivo analysis without tissue sampling.…”

Section: Challenges For Future Translation To the Clinicmentioning

confidence: 99%

Heart Valve Tissue Engineering: Concepts, Approaches, Progress, and Challenges

2006

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Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling.

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Cardiac-Specific Gene Expression Facilitated by an Enhanced Myosin Light Chain Promoter

Abstract: This new vector may be useful to validate therapeutic approaches in animal disease models and offers the perspective for selective expression of therapeutic genes in the diseased heart.

Cited by 37 publications

References 18 publications

Hrd1 and ER-Associated Protein Degradation, ERAD, Are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes

Hrd1 and ER-Associated Protein Degradation, ERAD, Are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes

Targeting Sarcoplasmic Reticulum Calcium ATPase by Gene Therapy

Heart Valve Tissue Engineering: Concepts, Approaches, Progress, and Challenges

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