FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction

Abstract

Mammalian cardiomyocytes have limited proliferation potential, and acutely injured mammalian hearts do not regenerate adequately. Instead, injured myocardium develops fibrosis and scarring. Here we show that FGF1͞p38 MAP kinase inhibitor treatment after acute myocardial injury in 8-to 10-week-old rats increases cardiomyocyte mitosis. At 3 months after injury, 4 weeks of FGF1͞p38 MAP kinase inhibitor therapy results in reduced scarring and wall thinning, with markedly improved cardiac function. In contrast, p38 MAP kinase inhibition alone fails to rescue heart function despite increased cardiomyocyte mitosis. FGF1 improves angiogenesis, possibly contributing to the survival of newly generated cardiomyocytes. Our data indicate that FGF1 and p38 MAP kinase, proteins involved in cardiomyocyte proliferation and angiogenesis during development, may be delivered therapeutically to enhance cardiac regeneration.cardiac regeneration ͉ fractional shortening ͉ Cyclin D2 ͉ Cyclin A ͉ angiogenesis

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…In contrast to previous reports on a negative role of p38 MAPK in mammalian and zebrafish heart regeneration [44,45], our data support that H 2 O 2 in the epicardium (Figure 1) is essential for elevating phosphorylation of Erk1/2 MAPK through repression of Dusp6 during zebrafish heart regeneration ( Figures 3-5 and 7). Our data are aligned well with the previous reports that H 2 O 2 directly oxidizes Dusp6 in TNFα-induced cell death and ovarian cancers, leading to ubiquitination and subsequent proteasome degradation of Dusp6 and thus aberrant Erk1/2 activation [37,38] (Figure 5).…”

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…These findings have supported a new paradigm, which suggests that the heart might be capable of repair and regrowth in response to extracellular mitogens. Consistent with this idea, it is known that FGF1 regulates cardiac remodeling by exerting a protective and proliferative effect after MI [18,19]. On the other hand, neuregulins play crucial roles in the adult cardiovascular system by inducing structural organization of sarcomeres, cell integrity, cell-cell adhesion [20], cell survival [21,22] and angiogenesis [23].…”

“…These strategies have been used mainly for the delivery of VEGF [14,[29][30][31], FGF1 [19] and FGF2 [32,33]. Although hydrogels represent an appealing class of delivery vehicles, technical difficulties related to injection of the gelatin hydrogel into the thin ventricular wall of infarcted rat hearts have been reported [34].…”

“…NRG1 regulates cardiovascular homeostasis during development and adulthood by stimulating recruitment and proliferation of cardiac progenitors and cardiomyocytes as well as inducing angiogenesis, vasculogenesis, and cardiac remodeling [24]. On the other hand, FGF1 is a potent cardiac mitogen capable of reducing damage-induced cardiac scarring [19]. Based on the putative activities of these two growth factors, we hypothesized that a combination therapy involving administration of both cytokines would be more beneficial than each individually; however, we did not observe a consistent synergistic effect in vitro or in vivo.…”

“…[19,24] Thus, to determine whether growth factor loaded MPs could have a similar effect, expression of Ki67 was examined in myocyte-specific enhancer factor 2c (MEF2c) + and cardiac troponin-T (cTnT) + cardiomyocytes. We observed a significant increase in the number of Ki67 + cardiomyocytes in the infarcted and peri-infarcted zones following treatment with NRG1-MP compared with NL-MP at 1 week ( Figure 5A) and 3 months ( Figure 5B) post-implantation (1.5-and 3.4-fold increases in Ki67 + cardiomyocytes/mm 2 at 1 week and 3 months, respectively).…”