Research Departments & Organizations
My laboratory is interested to understand at the cellular and molecular level, the growth regulatory mechanisms generated by the endothelium-cardiomyocyte communications that prevent pathological remodeling and heart failure. Our research is focused on the hypertrophic mechanisms regulated by the endotelium-released nitric oxide, Gi /Gq protein signaling and microRNAs.
Specialized Terms: Endothelium-Cardiomyocyte Communication; Myocardial Hypertrophy; Angiogenesis; Nitric Oxide; Gi/Gq Signaling; microRNAs
Extensive Research Description
Recent findings from our laboratory show that induction of myocardial angiogenesis promotes cardiomyocyte growth and myocardial hypertrophy through a novel nitric oxide (NO)-dependent mechanism leading to the degradation of regulator of G protein signaling type 4 (RGS4) thus relieving the repression of the Gβγ/PI3Kγ/Akt/mTORC1 pathway. The hypertrophy observed is physiological, preserves contractile function and is not accompanied by fibrosis or induction of markers associated with pathological hypertrophy. Our recent new data show that the angiogenesis driven hypertrophic response is associated with the up-regulation of microRNA miR-182 and miR-146b expression in cardiomyocytes.
The molecular and functional differences between pathological and physiological hypertrophy are not fully understood and an important unanswered question is whether the mechanisms responsible for the physiological hypertrophic response can be exploited to prevent pathological hypertrophy and heart failure in patients with left ventricle (LV) pressure overload.
Therefore to explore in more details this new role played by the vascular endothelium in controlling heart growth and function we aim to determine:
(1) The mechanism(s) through which the NO-RGS4-G protein axis mediates cardiomyocyte hypertrophy. The role of the Arg/N-end rule pathway in RGS4 degradation and activation of hypertrophic signaling through Gq and Gi proteins.
(2) The differential effects of angiogenesis NO-driven physiological hypertrophy versus G protein coupled receptor (GPCR)-driven pathological hypertrophy on miR-182 or miR-146b expression in cardiomyocytes.
(3) The contribution of endothelial NO-mediated RGS4 loss of function in promoting myocardial growth in a conditional heart specific mouse model of myocardial angiogenesis and whether mir-182 or miR-146b is necessary and sufficient for the hypertrophic response.
(4) The functional significance of endothelium-driven myocardial hypertrophy and whether a strategy of induction of angiogenesis that drives myocardial hypertrophy or angiogenesis with inhibition of hypertrophic response is beneficial during pathologic stress of pressure overload or myocardial infarct.
(5) The cardioprotective potential of miR-182 or miR-146b during the pathological stress of pressure overload.
- Growth regulatory mechanisms in the heart
- Endothelium-cardiomyocyte communications
- Hypertrophic mechanisms regulated by nitric oxide
- Gi /Gq protein signaling and hypertrophic response
- microRNAs in myocardial hypertrophy, angiogenesis and cardiac signaling
Cardiac Hypertrophy: Signaling and Cellular Crosstalk
Tirziu D., Cardiac Hypertrophy: Signaling and Cellular Crosstalk, 2018. In: Vasan R., Sawyer, D.(eds.) The Encyclopedia of Cardiovascular Research and Medicine, vol., pp. 434-450. Oxford: Elsevier 2018
miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart.
Li N, Hwangbo C, Jaba IM, Zhang J, Papangeli I, Han J, Mikush N, Larrivée B, Eichmann A, Chun HJ, Young LH, Tirziu D. miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart. Scientific Reports 2016, 6:21228. 2016
NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth.
Jaba IM, Zhuang ZW, Li N, Jiang Y, Martin KA, Sinusas AJ, Papademetris X, Simons M, Sessa WC, Young LH, Tirziu D. NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. The Journal Of Clinical Investigation 2013, 123:1718-31. 2013
Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching.
Tirziu D, Jaba IM, Yu P, Larrivée B, Coon BG, Cristofaro B, Zhuang ZW, Lanahan AA, Schwartz MA, Eichmann A, Simons M. Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching. Circulation 2012, 126:2589-600. 2012
Cell communications in the heart.
Tirziu D, Giordano FJ, Simons M. Cell communications in the heart. Circulation 2010, 122:928-37. 2010
Endothelium as master regulator of organ development and growth.
Tirziu D, Simons M. Endothelium as master regulator of organ development and growth. Vascular Pharmacology 2009, 50:1-7. 2009
Endothelium-driven myocardial growth or nitric oxide at the crossroads.
Tirziu D, Simons M. Endothelium-driven myocardial growth or nitric oxide at the crossroads. Trends In Cardiovascular Medicine 2008, 18:299-305. 2008
Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice.
Tirziu D, Chorianopoulos E, Moodie KL, Palac RT, Zhuang ZW, Tjwa M, Roncal C, Eriksson U, Fu Q, Elfenbein A, Hall AE, Carmeliet P, Moons L, Simons M. Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice. The Journal Of Clinical Investigation 2007, 117:3188-97. 2007