PARP1 adenovirus

High-mobility group box 1 (HMGB1) exhibits multiple functions depending on its subcellular localization, which is finely regulated by multiple post-translational modifications, such as acetylation. HMGB1 in the nucleus can prevent cardiac hypertrophy, while its exogenous protein has been shown to induce hypertrophic responses. Here, researchers explored the regulatory relationship between poly (ADP-ribose) polymerase 1 (PARP1) and HMGB1 in the process of pathological cardiac hypertrophy. Primary cultured neonatal rat cardiomyocytes (NRCMs) were incubated with three cardiac hypertrophy stimulants, including angiotensin II (Ang II), phenylephrine (PE), and isoproterenol (ISO), and cell surface area and mRNA expression of hypertrophy biomarkers were measured. The results showed that the catalytic activity of PARP1 was significantly enhanced, while HMGB1 was excluded from the nucleus. Overexpression of PARP1 through adenovirus PARP1 (Ad-PARP1) infection can promote the nuclear export of HMGB1, promote its secretion outside the cell, and aggravate cardiac hypertrophy, while overexpression of HMGB1 can alleviate this phenomenon. Similar results were obtained by PE treatment, while PARP1 silencing or its specific inhibitor AG14361 can significantly inhibit this effect. These studies provide new evidence that PARP1 binds to HMGB1 and accelerates its translocation from the nucleus to the cytoplasm, ultimately leading to cardiac hypertrophy.

To explore the effects of PARP1 and HMGB1 on cardiac hypertrophy, the researchers conducted a series of experiments. NRCMs were treated with adenovirus encoding PARP1 (Ad-PARP1) for 48 hours. The control group was incubated with an equal amount of green fluorescent protein (Ad-GFP). In the Ad-PARP1 group, cell surface area and mRNA expression of ANF and BNP were significantly increased (Figure 1a, b), indicating that PARP1 overexpression induced cardiac hypertrophy. In contrast, endogenous PARP1 knockdown or its specific inhibitor AG14361 alleviated the PE-induced increase in cell surface area and upregulation of ANF and BNP mRNA (Figure 1c, d), indicating that the reduction of PARP1 reversed PE-induced cardiac hypertrophy. To explore the role of HMGB1 in PE-stressed cardiac hypertrophy, NRCMs were transfected with HMGB1 plasmid, whether or not they were incubated with PE. As shown in Figure 1e, f, HMGB1 overexpression significantly alleviated the hypertrophic response induced by PE, which can be observed by changes in cell surface area and ANF and BNP mRNA levels. In addition, both PE treatment and Ad-PARP1 infection significantly aggravated cardiac hypertrophy, as manifested by an increase in cell surface area and increased ANF and BNP mRNA levels, while HMGB1 overexpression significantly inhibited this effect (Figure 1e, f). These findings suggest that HMGB1 is involved in PARP1-induced cardiac hypertrophy.

Figure 1. The effect of PARP1 and HMGB1 on PE-induced cardiac hypertrophy. (Li Q, et al., 2019)