We demonstrated that short-term treatment with a DPP4 inhibitor, vildagliptin, prevented LV hypertrophy caused by continuous infusion of isoproterenol. These effects were accompanied by the amelioration of expression of genes associated with glucose uptake and inflammation. Although cardiac catheterization showed that vildagliptin did not significantly improve LV diastolic dysfunction in isoproterenol-treated rats, this study indicated that vildagliptin has potential for preventing LV hypertrophy independent of blood pressure.
Regarding the mechanisms underlying the protective effect of vildagliptin in preventing isoproterenol-induced LV hypertrophy in this study, one possible explanation is that vildagliptin may reduce inflammation in the heart. A previous study showed that isoproterenol induces expression of mRNAs that encode myocardial pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β . Our previous study revealed a direct effect of TNF-α on cardiac hypertrophy in cultured cardiomyocytes . Thus, TNF-α and IL-6 are likely to be important factors in the induction of hypertrophy [26, 27]. In our current study, vildagliptin reduced the expression of Tnfa and Il6 mRNAs in myocardial tissue of isoproterenol-treated rats. Similarly, recent studies demonstrated the effect of DPP4 inhibitors on the reduction of pro-inflammatory cytokines in macrophages, visceral adipose tissue, and atherosclerotic plaques [28, 29]. Furthermore, vildagliptin suppressed the increase in Igf1 expression induced by isoproterenol in our rat model. Recent studies showed the involvement of IGF1 in cardiomyocyte hypertrophy [30, 31]. Thus, a change in cytokine expression by vildagliptin may contribute to the prevention of LV hypertrophy. Another possibility is that increased active GLP-1 levels by vildagliptin directly influences LV hypertrophy. In several previous experiments in rats, oral vildagliptin was used at a dose of 3 to 60 mg/kg/day [11, 32]. We selected the dose of 30 mg/kg/day of vildagliptin in this study and confirmed that this dosage increased the GLP-1 level at the fasting state by 2-fold compared with the control group. A study showed that recombinant GLP-1 infusion for 14 days reduces blood pressure, LV hypertrophy, and LV fibrosis in Dahl salt-sensitive rats . Another group has reported that administration of a GLP-1 analog diminishes cardiac hypertrophy and blood pressure in obese mice exhibiting insulin resistance . In both studies, it was difficult to discriminate the effect of GLP-1 on the protection of LV hypertrophy from its blood pressure–lowering effects. Taken together, these results suggest that the anti-inflammatory effect and suppression of IGF1 by vildagliptin in the heart at least partly counters LV hypertrophy.
In this study, although LVEDP was significantly lower in the ISO-VL group than in the ISO group, other catheter-related parameters such as maximum dp/dt, minimum dp/dt were similar between the two groups. Thus, this study failed to demonstrate that vildagliptin ameliorated LV diastolic function in the ISO-VL group. Energy metabolism, however, switches from fatty acid oxidation to carbohydrate oxidation in hypertrophied hearts , and thus the increase in expression of Glut4 mRNA by vildagliptin may improve glucose uptake in cardiomyocytes and then ameliorate ATP synthesis through carbohydrate oxidation. In fact, treatment with a DPP4 inhibitor, sitagliptin, improves insulin resistance and increases cardiac GLUT4 protein and mRNA abundance in spontaneously hypertensive rats . In hypertrophied hearts, the shift in MHC isoform composition from α- to β-MHC has also been reported . Our finding that expression of cardiac α-MHC (Myh6) mRNA decreased in isoproterenol-treated rats is consistent with those previous data. The improvements in energy production have beneficial effects on failing hearts and may upregulate Myh6 expression. In this study, although insulin sensitivity was not assessed, rats in the ISO and vehicle groups exhibited similar glucose tolerance patterns. Given that vildagliptin lowered the AUCs in both isoproterenol-treated and vehicle-treated rats, vildagliptin may exert favorable effects on insulin signaling in isoproterenol-treated hearts. This study also demonstrated that decreased inflammatory cytokines may contribute to dysregulated cardiac signaling. Other studies have shown that TNF-α causes cardiac insulin resistance by inducing degradation of insulin receptor substrate protein 1, which is critical for cardiac insulin signaling [38, 39]. Thus, reduced expression of Tnfa mRNA by vildagliptin, as shown in our present study, also partly contributes to the increase in energy production in isoproterenol-treated hearts. On the other hand, histological analyses in this study showed that vildagliptin significantly suppressed perivascular fibrosis in isoproterenol-treated hearts but did not affect angiogenesis. One study showed that vildagliptin reverses angiogenesis in diabetic murine hearts by increasing the activity of stromal cell–derived factor-1α, which is a substrate of DPP4 . The lack of change in angiogenesis in the isoproterenol-infused rat model may explain why diastolic function is not significantly improved.
DPP4 is widely expressed on the surface of endothelial cells and immune cells such as lymphocytes and monocytes [40–42]. DPP4 inhibitors exert their effects by inhibiting enzymatic degradation of GLP-1; however, recent studies reported non-enzymatic functions for DPP4 . For instance, cell-surface DPP4 regulates inflammatory responses in innate immune cells such as monocytes and dendritic cells through the incretin-independent pathway [44, 45]. In endothelial cells, DPP4-mediated signaling pathways result in phosphorylation of endothelial nitric oxide synthase . The distinct role of DPP4 in cardiac tissue remains unknown, but further examination will shed light on the novel functions of DPP4 inhibitors in the heart.
Although the effects of DPP4 inhibitors on LV hypertrophy in humans have not been fully elucidated, the moderate blood pressure–lowering effect of DPP4 inhibitor may have favorable effect on LV hypertrophy in this clinical setting . The mechanism of this effect has been attributed to increased diuresis and natriuresis owing to inhibition of sodium reabsorption from the proximal renal tubules . Another mechanism for the blood pressure–lowering effects of DPP4 inhibitors is peripheral vasodilatation and decreased peripheral vascular resistance. Recently, van Poppel et al. showed that vildagliptin improves endothelial function in patients with type 2 diabetes . Moreover, a recent clinical study indicated that endothelial dysfunction is closely associated with HFpEF , and thus favorable effects of DPP4 inhibitors on the vascular system suggest a therapeutic potential for preventing LV hypertrophy and HFpEF in humans.
The elevation of the circulating GLP-1 level has a potential role in cardioprotection, but we did not explore the direct effect of GLP-1 on hypertrophy of cardiomyocytes in this study. Further, a wide range of peptides are considered to be substrates of DPP4. Comprehensive analysis of the effect of DPP4 inhibitors on the substrates in hypertrophied hearts will help to identify the underlying mechanisms. Second, our finding indicated the potential role of vildagliptin on the protection, but not regression, of LV hypertrophy. In clinical practice, it would be of interest to see if administration of DPP4 inhibitor has benefits for patients with existing LV hypertrophy. Further study is warranted to address this question. Finally, It is necessary to understand the role of DPP4 itself in cardiac hypertrophy to address the potential role of DPP4 inhibitors as therapeutics.
In conclusion, a DPP4 inhibitor, vildagliptin, prevented LV hypertrophy caused by continuous exposure to isoproterenol in rats. This finding suggests the possibility of using a DPP4 inhibitor to prevent LV hypertrophy in humans.