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The cyclin-dependent kinase inhibitor p21 CIP1/WAF1 (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice ( p21 KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21 KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21 KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21 KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0 mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10 mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors (FGFs) mediate key cardiac functions from development to homeostasis and disease. The current research was to explore the effects of FGF12 in the fibrosis of cardiac function and heart failure, and whether FGF12 alleviated cardiac fibrosis via inhibition of oxidative stress. Ligation of left coronary artery in mice induced heart failure and myocardial infarction (MI). Angiotensin II (Ang II) was administered to cardiac fibroblasts (CFs). FGF12 upregulation or FGF12 transgenic (Tg) mice could improve cardiac dysfunction of MI mice, and attenuated cardiac fibrosis of heart failure induced by MI in mice. FGF12 overexpression suppressed the increases of collagen I, collagen III and fibronectin which was induced by Ang II in CFs. The oxidative stress was enhanced in the heart of MI mice and CFs treated with Ang II, and these enhances were attenuated via FGF12 overexpression. Superoxide dismutase (SOD) overexpression inhibited the enhancements of collagen I, collagen III and fibronectin in the heart of MI mice, and in the CFs treated with Ang II. Overexpression of nicotinamide adenine dinucleotide phosphate oxidases (Nox1) reversed the attenuating influences of FGF12 on the enhancements of collagen I, collagen III and fibronectin in the CFs induced by Ang II. These outcomes showed that FGF12 upregulation can improve cardiac dysfunction and heart fibrosis of heart failure. FGF12 attenuates oxidative stress to suppress the cardiac fibrosis. • FGF12 upregulation improved cardiac dysfunction of heart failure. • FGF12 upregulation alleviated heart fibrosis of heart failure. • FGF12 attenuates oxidative stress to suppress the cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies showed that angiotensin-(1–7) [Ang-(1–7)] attenuates cardiac remodeling by reducing both interstitial and perivascular fibrosis. Although a high affinity binding site for Ang-(1–7) was identified on cardiac fibroblasts, the molecular mechanisms activated by the heptapeptide hormone were not identified. We isolated cardiac fibroblasts from neonatal rat hearts to investigate signaling pathways activated by Ang-(1–7) that participate in fibroblast proliferation. Ang-(1–7) reduced 3H-thymidine, -leucine and -proline incorporation into cardiac fibroblasts stimulated with serum or the mitogen endothelin-1 (ET-1), demonstrating that the heptapeptide hormone decreases DNA, protein and collagen synthesis. The reduction in DNA synthesis by Ang-(1–7) was blocked by the AT(1–7) receptor antagonist [d-Ala7]-Ang-(1–7), showing specificity of the response. Treatment of cardiac fibroblasts with Ang-(1–7) reduced the Ang II- or ET-1-stimulated increase in phospho-ERK1 and -ERK2. In contrast, Ang-(1–7) increased dual-specificity phosphatase DUSP1 immunoreactivity and mRNA, suggesting that the heptapeptide hormone increases DUSP1 to reduce MAP kinase phosphorylation and activity. Incubation of cardiac fibroblasts with ET-1 increased cyclooxygenase 2 (COX-2) and prostaglandin synthase (PGES) mRNAs, while Ang-(1–7) blocked the increase in both enzymes, suggesting that the heptapeptide hormone alters the concentration and the balance between the proliferative and anti-proliferative prostaglandins. Collectively, these results indicate that Ang-(1–7) participates in maintaining cardiac homeostasis by reducing proliferation and collagen production by cardiac fibroblasts in association with up-regulation of DUSP1 to reduce MAP kinase activities and attenuation of the synthesis of mitogenic prostaglandins. Increased Ang-(1–7) or agents that enhance production of the heptapeptide hormone may prevent abnormal fibrosis that occurs during cardiac pathologies. [Copyright &y& Elsevier]

Urotensin II (UII) is a potential mediator in the pathogenesis of cardiovascular disease, and inhibition of its actions at the urotensin receptor (UT) has been shown to improve cardiac function and structural changes of the myocardium in a model of myocardial infarction. In this study we utilized a model of pressure-overload hypertrophy induced by abdominal aortic constriction (AAC) which resulted in hypertrophy, increased fibrosis and impaired diastolic and systolic function. These changes were associated with a 4-fold increase in UII protein expression in the myocardium. Treatment of animals with a selective UT (SB-657510) antagonist for 20 weeks at a dose of 1500ppm did not improve cardiac function as assessed by echocardiography and pressure–volume loop analysis, nor did it inhibit left ventricular hypertrophy or fibrosis. We hypothesize that other neurohumoral pathways may have a greater involvement in the pathogenesis of this model. Targeting the UII system appears to be insufficient to observe a beneficial outcome. [Copyright &y& Elsevier]

• Lack of therapies addressing cardiac fibrosis in myocardial infarction patients. • Ghrelin improves cardiac function and remodeling after myocardial infarction. • Nrf2 counteracts pro-fibrotic signals responsible for cardiac fibrosis. • Ghrelin attenuates cardiac fibrosis and oxidative stress by activating Nrf2. To evaluate the role of ghrelin in cardiac fibrosis after myocardial infarction (MI) and to investigate the underlying mechanisms of ghrelin-regulated Nrf2/NADPH/ROS pathway-mediated cardioprotection, the profile of Nrf2, fibrosis markers, and oxidative stress markers were characterized in a rat model of MI and Angiotensin II (Ang II)-stimulated cardiac fibroblasts (CFs). The effects of ghrelin on cardiac function, fibrosis and oxidative stress were investigated after MI in vivo. The role of ghrelin in CF migration and proliferation was evaluated in Ang II-stimulated CFs in vitro. Inhibition of ghrelin receptors using the antagonist, d -Lys3-GHRP-6, in addition to ghrelin was employed in MI and CFs to investigate the direct effect of ghrelin on cardiac fibrosis. Loss function of Nrf2 in CFs was performed to investigate the effect of ghrelin-regulated Nrf2 on oxidative stress and cardiac fibrosis. Ghrelin improved the post-MI cardiac function and reduced cardiac fibrosis. This phenotype is associated with the upregulation of Nrf2 and downregulation of fibrotic proteins, NADPH oxidase and ROS production. In line with in vivo findings, ghrelin attenuated Ang II-stimulated CF migration, proliferation, and oxidative stress in vitro. Inhibition of the ghrelin receptor or knockdown of Nrf2 abolished the beneficial effects of ghrelin on MI or Ang II-stimulated cardiac fibroblasts. In conclusion, ghrelin ameliorates post-MI and Ang II-induced cardiac fibrosis by activating Nrf2, which in turn inhibits the NADPH/ROS pathway. [ABSTRACT FROM AUTHOR]