Novel Cardioprotective Role of a Small Heat-Shock Protein, Hsp20, Against Ischemia/Reperfusion Injury

Abstract

Background-Heat-shock proteins (Hsps) have been shown to render cardioprotection from stress-induced injury; however, little is known about the role of another small heat-shock protein, Hsp20, which regulates activities of vasodilation and platelet aggregation, in cardioprotection against ischemia injury. We recently reported that increased expression of Hsp20 in cardiomyocytes was associated with improved contraction and protection against ␤-agonistinduced apoptosis. Methods and Results-To investigate whether overexpression of Hsp20 exerts protective effects in both ex vivo and in vivo ischemia/reperfusion (I/R) injury, we generated a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20 (10-fold). TG and wild-type (WT) hearts were then subjected to global no-flow I/R (45 minutes/120 minutes) using the Langendorff preparation. TG hearts exhibited improved recovery of contractile performance over the whole reperfusion period. This improvement was accompanied by a 2-fold decrease in lactate dehydrogenase released from the TG hearts. The extent of infarction and apoptotic cell death was also significantly decreased, which was associated with increased protein ratio of Bcl-2/Bax and reduced caspase-3 activity in TG hearts. Furthermore, in vivo experiments of 30-minute myocardial ischemia, via coronary artery occlusion, followed by 24-hour reperfusion, showed that the infarct region-to-risk region ratio was 8.1Ϯ1.1% in TG hearts (nϭ7), compared with 19.5Ϯ2.1% in WT hearts (nϭ11, PϽ0.001). Conclusions-Our data demonstrate that increased Hsp20 expression in the heart protects against I/R injury, resulting in improved recovery of cardiac function and reduced infarction. Thus, Hsp20 may constitute a new therapeutic target for ischemic heart diseases.

Heat shock protein 20 (HSPB6) regulates apoptosis in human hepatocellular carcinoma cells: Direct association with Bax

“…In normal mouse heart, overexpressed HSP20 reportedly interacts with the Bax protein and protects the heart against ischemia/reperfusion injury (19). It has also been reported that acute expression of HSP20 in rat cardiomyocytes is protective against apoptosis (20).…”

Small heat shock proteins in ageing and age-related diseases

“…Furthermore, HSPB1 controls the release of second mitochondria-derived activator of caspases (Smac), which promotes apoptosis via caspase activation, and also plays important role in the p53 pathway, underlining its crucial role in apoptosis and in the regulation of cellular senescence (Bakthisaran et al 2015;Chauhan et al 2003;O'CallaghanSunol et al 2007;. Similarly, alpha-crystallins (HSPB4 and HSPB5) and HSPB6 prevent apoptotic cell death through interaction with pro-apoptotic proteins of the Bcl-2 family, such as Bax and Bcl-X(S), intercepting their translocation from cytosol into mitochondria (Fan et al 2005b;Mao et al 2004). Additionally, alpha-crystallins preserve mitochondrial integrity and inhibit apoptosis by interacting with cytochrome c and caspase subtypes and by repressing caspase-3 activation (Bakthisaran et al 2015;Mao et al 2004;McGreal et al 2012).…”

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

“…HSP20 protects the heart against sepsis-and endotoxin-induced cardiac dysfunction in mice [53] and overexpression of HSP20 reduced apoptosis upon ischemia/reperfusion (I/R) injury [54]. The cardioprotective effect of HSP20 is due to a phosphorylation of serine 16 by PKA.…”

“…Overexpression of a phosphomimic (HSP20-S16D), i.e. constitutively phosphorylated HSP20, in adult cardiac myocytes inhibited apoptosis [54,55]. HSP20…”