## 4 Discussion
### Heart Remodeling Is Related to Ang II  
The observed heart and cardiomyocyte hypertrophy in the Ang II-treated control and Ang II-treated db/db mice seem to be dependent on Ang II signaling. A similar effect of Ang II on cardiac hypertrophy was observed by [PERSON] et al. [52]. Our results indicate that the hypertrophic heart phenotype in the Ang II-treated db/db mice was associated with cardiomyocyte hypertrophy, increased fibrosis and myocardial tissue edema. Such features of cardiac remodeling are consistent with the Ang II influence described in the literature, as reviewed by [PERSON] et al. [14]. Ang II induces an inflammatory response and oxidative stress [64; 65], which further triggers fibrosis and cardiomyocyte hypertrophy [66; 67; 68]. In fact, inflammatory signaling in obesity and diabetes, which is considered a state of chronic subclinical sterile inflammation, may stimulate cardiac hypertrophy [69; 70] and Ang II could further intensify this process [66; 67; 68]. Of note, fewer macrophages infiltrated the myocardial interstitium of the db/db mice compared to the db/db mice treated with Ang II and fewer inflammatory cells were found in the myocardial interstitium of the db/db compared to the Ang II-treated control mice. In other words, the number of interstitially distributed inflammatory cells (without scars and granulation tissue) increased significantly under Ang II treatment in the control versus db/db mice. Similarly, [PERSON] et al. [52] reported significantly increased numbers of inflammatory cells (CD45\({}^{+}\)) in control mice treated with Ang II, whereas the levels of these cells remained unchanged in our study in the db/db and Ang II-treated db/db vs. control mice. These results are in slight contrast to ours, probably due to the counting of inflammatory cells in areas of the myocardium including granulation tissue/scars and presumably due to the age of animals and dosesof Ang II. The intensity of the inflammatory cell infiltration and inflammatory cell profile may change during the progression of disease. For example, [PERSON] et al. [71] reported an enormous increase in inflammatory cells (polymorphonuclear cells) in db/db mice vs. control at 11 weeks. Moreover, [PERSON] et al. did not observe altered expression of mRNA for the inflammatory marker nuclear factor-kappa B inhibitor-alpha in the myocardium and found a significant decline in the IL-6 mRNA levels in db/db mice vs. control mice. In addition, [PERSON]'s group reported that the level of cardiac phosphorylated AMP-activated protein kinase (pAMPK) was lower in Ang II-treated db/db mice compared to controls, which did not confirm cardiac metabolic remodeling [52]. It is known that Ang II action involves TGF signaling in fibroblasts and cardiomyocytes, thus inducing both cardiac fibrosis and cardiomyocyte hypertrophy, and is involved in the inflammatory response (reviewed in [72]). Moreover, cardiomyocyte hypertrophy in Ang II-treated db/db mice might depend on impaired leptin signaling [73; 74], which is a characteristic symptom in \(\text{Lepr}^{\text{db/db}}\) mice [53; 75]. Leptin has been reported to prevent cardiomyocyte hypertrophy by a pathway involving stimulation of cardiac nitric oxide signaling [76; 77]. In our study, this pathway did not seem to influence Ang II-triggered cardiomyocyte hypertrophy since we also detected hypertrophy in the Ang II-treated control animals with the functional leptin receptor. Myocardial fibrosis in the diffuse interstitial and perivascular forms, as well as within the microscopic scars, was only present in the Ang II-treated control and Ang II-treated db/db mice, albeit in the db/db animals (vs. control) a significantly increased diffuse interstitial fibrosis was also found in the inner half (endocardial) of the myocardial wall (Figure 6A). It is known that these types of fibrosis are associated with pathological cardiac remodeling in hypertension [78].