Heat Shock Cognate Protein 70 Is Essential for Akt Signaling in Endothelial Function

Abstract

Objective-Heat shock protein 70s (Hsp70s) are molecular chaperones that protect cells from damage in response to various stress stimuli. However, the functions and mechanisms in endothelial cells (ECs) have not been examined. Herein, we investigate the role of Hsp70s, including heat shock cognate protein 70 (Hsc70), which is constitutively expressed in nonstressed cells (ie, ECs). Hsp72, a member of the Hsp70 family, protects cells, tissues, and organs from various harmful conditions in blood vessels. Previous work 4,5 has shown that an increase in levels of a particular Hsp72, induced by heat stress, is associated with the protection of ventricular and endothelial function after ischemia-reperfusion injury. Several studies 6 -9 have been reported that upregulation of Hsp72 in cells by gene transfer greatly increases the resistance of myocardial cells in vitro and in transgenic mice. On the other hand, deletion of Hsp72 leads to dysfunctional cardiomyocytes and impaired stress response of Hsp72-knockout hearts against ischemia/ reperfusion. 10 Thus, Hsp72 may be expected to play a protective role by reducing the risk of myocardial cell injury and exerting its beneficial effects on endothelial function. However, little is known about the functional role of Hsp70 family members in response to ischemic injury. Methods and Results-TheThe human Hsp70 family, which is the largest and most conserved Hsp family, contains at least eight homologous chaperone proteins. This family includes the Hsp72-inducible protein and constitutively expresses the heat shock cognate protein 70 (Hsc70) isoform, both of which are localized to the cytoplasm. Two members of the Hsp70 family, Hsc70 and Hsp72, have a high degree of sequence homology (86% sequence identity), and both proteins copurify with one another. Hsc70 is abundantly and ubiquitously expressed in all cells, whereas Hsp72 is expressed only at low levels in most unstressed healthy cells and tissues. However, its expression is rapidly induced by a variety of physical and chemical stresses; therefore, it is often called the major stress-inducible Hsp70. It is suggested that Hsp72 and Hsc70 can substitute for each other in healthy cells, whereas Hsp72 expression is essential for certain cells to respond to some cytotoxic factors. There are several chaperone mechanisms based on inducible Hsp72 and constitutive Hsc70. Although both bind to misfolded proteins, newly synthesized polypeptides (ie, Hsp72 and Hsc70) function in the cytosol, suggesting that they display specificity for their client proteins or, alternatively, serve particular chaperone-independent functions. 11 Previous studies mainly analyzed Hsp72 under vari- ous stress conditions; however, there is little research on Hsc70 in the cardiovascular system. In the present study, we investigated whether Hsp70s modulate the angiogenic process. Recently, it has been reported that RNAi-mediated knockdown of human Hsc 70 A12B, a member of the Hsp70 family, disrupted normal zebra fish blood vessel development and inhibited in ...

Heat therapy promotes the expression of angiogenic regulators in human skeletal muscle

“…This highly conserved family of proteins function as molecular chaperones, and HSPs are involved in multiple cellular activities, including angiogenesis signaling (58,67,71). For instance, members of the HSP70 and HSP90 families have been reported to modulate angiogenesis in skeletal muscle (58,67).…”

“…Second, repeated treatment with far infrared dry sauna increases skeletal muscle capillary density in a mouse model of PAD (1,40) and diabetes (26) and in rats treated with glucocorticoids (43). This angiogenic response in the heart and in skeletal muscle is closely coupled with increased expression of heat shock proteins (HSPs), molecular chaperones that are known to modulate the angiogenic process (40,67,71). Third, endothelial cells exposed to mild heat stress have an enhanced capacity for vascular tube formation, which is indicative of angiogenesis activity (60).…”

Biochemical Effects of Exercise on a Fasciocutaneous Flap in a Rat Model

“…26,27 This is juxtaposed to the RAG, which again exhibited increased proapoptotic proteins and decreased Bcl-2 ( Figure 3B). Although the exact mechanism for this apparent induction noted by exercising rats (Figure 4) is not entirely clear, such activation has been previously described in response to exercise-induced stress 17,28 and likely reflects increased VEGFR activation in response to exercise (eFigure 2 in the Supplement). Perhaps cells exposed to higher levels of stress during more strenuous exercise can escalate VEGF synthesis de novo, prolong VEGF messenger RNA half-life, or protect existing VEGF molecules from degradation and thus sustain VEGFR signaling (eFigure 3 in the Supplement).…”

“…These cascades also induce angiogenesis, increase vascular permeability, and enhance autocrine VEGF production. [14][15][16] Similarly, induction of various heat shock proteins promotes hypoxic tolerance and increases cell survival via modulation of the PI3K/Akt signaling 17 and other cell death-related cellular mechanisms. 18 Thus, creating an oxygen gradient elicits potent molecular responses that promote cell adaptation to injury and expedite wound repair.…”

PKCι counteracts oxidative stress by regulating Hsc70 in an esophageal cancer cell line

“…Hsc70 functions as a chaperone by trafficking proteins to different cellular compartments (Pilon and Schekman 1999) and is important in endocytosis (de Waegh and Brady 1989). Hsc70 is also involved in Akt (Shiota et al 2010;Chen et al 2011) and NF-κB signaling (Lim et al 2008) and has been shown to regulate the Dbl oncoprotein (Kauppinen et al 2005) and Bim mRNA (Matsui et al 2007). Importantly, Hsc70 also regulates cell survival (Powers et al 2008) and confers protection from several forms of cellular stresses, such as viral infection (Yan et al 2010), metabolic stress (Williams et al 1993), and oxidative stress (Chong et al 1998;Dastoor and Dreyer 2000;Su et al 1999).…”