Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling.
Although Smad3 is a key mediator of fibrosis, the functional role of Smad3 in hypertensive cardiovascular disease remains unclear. The present study tested the hypothesis that angiotensin II may activate the transforming growth factor-beta/Smad3 pathway to mediate hypertensive cardiac remodeling in Smad3 knockout (KO) and wild-type mice by subcutaneous angiotensin II infusion and in the primary culture of Smad3 KO cardiac fibroblasts. Fourteen days after angiotensin II infusion, both Smad3 KO and wild-type mice developed equal levels of high blood pressure. However, hypertensive cardiac fibrosis and inflammation were developed in Smad3 wild-type but not in Smad3 KO mice. This was demonstrated by the findings that mice lacking Smad3 were protected against a fall in left ventricular ejection fraction (P<0.05), an increase in left ventricular mass (P<0.05), and the development of cardiac fibrosis and inflammation, including upregulation of transforming growth factor-beta1, connective tissue growth factor, collagen I/III, alpha-smooth muscle actin, interleukin 1beta, tumor necrosis factor-alpha, monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and an increase in macrophage and T-cell infiltration in left ventricular tissues (all P<0.01, respectively). Additional studies in vitro also revealed that angiotensin II-induced cardiac fibrosis and inflammation were prevented in Smad3 KO cardiac fibroblasts. Inactivation of both Smad3 and nuclear factor kappaB/p65 signaling pathways was a key mechanism by which Smad3 KO mice were protected from angiotensin II-mediated hypertensive cardiac remodeling. In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease.
Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Xiao R
XR
Huang
Arthur C K
AC
Chung
Fuye
F
Yang
Wensheng
W
Yue
Chuxia
C
Deng
Chu Pak
CP
Lau
Hung Fat
HF
Tse
Hui Y
HY
Lan
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D004452:Echocardiography; D017353:Gene Deletion; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013318:Stroke Volume; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II