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Articles by H Osinska
Total Records ( 2 ) for H Osinska
  A Maloyan , J Sayegh , H Osinska , B. H. L Chua and J. Robbins
 

Rationale: Transgenic mice with cardiac specific overexpression of mutated B-crystallin (CryABR120G) display Desmin-related myopathy (DRM) with dilated cardiomyopathy and heart failure. Our previous studies showed the presence of progressive mitochondrial abnormalities and activation of apoptotic cell death in CryABR120G transgenic hearts. However, the role of mitochondrial dysfunction and apoptosis in the overall course of the disease was unclear.

Objective: We tested the hypothesis that prevention of apoptosis would ameliorate CryABR120G pathology and decrease morbidity.

Methods and Results: We crossed CryABR120G mice to transgenic mice with cardiac specific overexpression of Bcl-2. Sustained Bcl-2 overexpression in CryABR120G hearts prolonged CryABR120G transgenic mice survival by 20%. This was associated with decreased mitochondrial abnormalities, restoration of cardiac function, prevention of cardiac hypertrophy, and attenuation of apoptosis. CryABR120G misfolded protein aggregation was significantly reduced in the double transgenic. However, inhibition of apoptotic signaling resulted in the upregulation of autophagy and alternative death pathways, the net result being increased necrosis.

Conclusion: Although Bcl-2 overexpression prolonged life in this DRM model, in the absence of apoptosis, another death pathway was activated.

  R. B Hinton , J Adelman Brown , S Witt , V. K Krishnamurthy , H Osinska , B Sakthivel , J. F James , D. Y Li , D. A Narmoneva , R. P Mecham and D. W. Benson
  Rationale:

Elastin is a ubiquitous extracellular matrix protein that is highly organized in heart valves and arteries. Because elastic fiber abnormalities are a central feature of degenerative valve disease, we hypothesized that elastin-insufficient mice would manifest viable heart valve disease.

Objective:

To analyze valve structure and function in elastin-insufficient mice (Eln+/–) at neonatal, juvenile, adult, and aged adult stages.

Methods and Results:

At birth, histochemical analysis demonstrated normal extracellular matrix organization in contrast to the aorta. However, at juvenile and adult stages, thin elongated valves with extracellular matrix disorganization, including elastin fragment infiltration of the annulus, were observed. The valve phenotype worsened by the aged adult stage with overgrowth and proteoglycan replacement of the valve annulus. The progressive nature of elastin insufficiency was also shown by aortic mechanical testing that demonstrated incrementally abnormal tensile stiffness from juvenile to adult stages. Eln+/– mice demonstrated increased valve interstitial cell proliferation at the neonatal stage and varied valve interstitial cell activation at early and late stages. Gene expression profile analysis identified decreased transforming growth factor-β–mediated fibrogenesis signaling in Eln+/– valve tissue. Juvenile Eln+/– mice demonstrated normal valve function, but progressive valve disease (predominantly aortic regurgitation) was identified in 17% of adult and 70% of aged adult Eln+/– mice by echocardiography.

Conclusions:

These results identify the Eln+/– mouse as a model of latent aortic valve disease and establish a role for elastin dysregulation in valve pathogenesis.

 
 
 
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