Heme oxygenase‐1 (HO‐1) inhibits postmyocardial infarct remodeling and restores ventricular function

Abstract

Protein misfolding and aberrant aggregation are associated with many severe disorders, such as neural degenerative diseases, desmin-related myopathy (DRM), and congestive heart failure. Intrasarcoplasmic amyloidosis and increased ubiquitinated proteins are observed in human failing hearts. The pathogenic roles of these derangements in the heart remain unknown. The ubiquitin-proteasome system (UPS) plays a central role in intracellular proteolysis and regulates critical cellular processes. In cultured cells, aberrant aggregation by a mutant (MT) or misfolded protein impairs the UPS. However, this has not been demonstrated in intact animals, and it is unclear how the UPS is impaired. Cross-breeding UPS reporter mice with a transgenic mouse model of DRM featured by aberrant protein aggregation in cardiomyocytes, we found that overexpression of MT-desmin but not normal desmin protein impairs UPS proteolytic function in the heart. The primary defect does not appear to be in the ubiquitination or the proteolytic activity of the 20S proteasome, because ubiquitinated proteins and the peptidase activities of 20S proteasomes were significantly increased rather than decreased in the DRM heart. Therefore, the defect resides apparently in the entry of ubiquitinated proteins into the 20S proteasome. Consistent with this notion, key components (Rpt3 and Rpt5) of 19S proteasomes were markedly decreased, while major components of 20S proteasomes were increased. Additional experiments with HEK cells suggest that proteasomal malfunction observed in MT-desmin hearts is not secondary to cardiac malfunction or to disruption of desmin filaments. Thus, UPS impairment may represent an important pathogenic mechanism underlying cardiac disorders with abnormal protein aggregation.

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

“…The enzymatic activity of HO-1 is often stimulated in responses to multiple stimuli such as UV radiation, lipopolysaccharide (LPS), heat shock and heavy metals [28] . Increased HO-1 activity is found protective against inflammation, excessive cell proliferation and interstitial fibrosis [29] .…”

Oxidative stress-inducible lentiviral vectors for gene therapy

“…5 Nevertheless, HO-1 has been used for gene therapy in several experimental animal models of CVD. 10,11,27,28 In the study by Pachori et al 10 Oxidative stress-inducible vectors H Hurttila et al significant induction of endogenous HO-1 was observed, yet HRE-regulated HO-1 overexpression provided an additional benefit. In our study, both in controls as well as 2 Â GCLM-HO-1-transduced HUVECs, 15d-PGJ 2 significantly attenuated TNF-a-induced NF-kB activation and VCAM-1 expression, but the effect was greater in HO-1-transduced cells (Figure 6).…”

Differential internalization and nuclear uncoating of self-complementary adeno-associated virus pseudotype vectors as determinants of cardiac cell transduction

“…AAV vectors have already been employed for therapeutic gene transfer into the myocardium in several animal models of human cardiovascular diseases. [1][2][3][4][5][6][7][8][9][10][11][12] Multiple AAV serotypes have been isolated in recent years which show grossly different tissue and organ tropisms. [14][15][16][17][18][19][20] This may be due to different cellular receptor affinities of the respective AAV virions, but for only few of the currently known AAV types the cellular receptors are currently known.…”