Cell Communication; Endothelium, Vascular; Heart Diseases; Heart Failure; MicroRNAs; Endothelium-Dependent Relaxing Factors; Cell Enlargement; Gene Regulatory Networks
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
Nitric Oxide-Regulated RGS4 loss of function coordinates vasculature and cardiomyocyte growth
Jaba IM, Zhuang ZW, Li N, Jiang Y, Martin K, Sinusas AJ, Papademetris X, Simons M, Sessa W, Young L, Tirziu D. Nitric Oxide-Regulated RGS4 loss of function coordinates vasculature and cardiomyocyte growth. J Clin Invest. 2013;123:1718-1731. PMID: 23454748
Endothelial NFkB -dependent regulation of arteriogenesis and branching
Tirziu D, Jaba IM, Yu P, Larrivée B, Coon BG, Cristofaro B, Zhuang ZW, Anthony A. Lanahan AA, Martin A. Schwartz MA, Eichmann A, Simons M. Endothelial NFkB -dependent regulation of arteriogenesis and branching. Circulation. 2012;126:2589-2600. PMID: 23091063
Cell communications in the heart
Tirziu D, Giordano FJ, Simons M. Cell communications in the heart. Circulation. 2010;122:928-37. PMID: 20805439
Endothelium as master regulator of organ development and growth
Tirziu D, Simons M. Endothelium as master regulator of organ development and growth. Vascul Pharmacol. 2009;50:1-7. PMCID: PMC2630387
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 Cardiovasc Med. 2008;18:299-305. PMCID: PMC2692333
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. J Clin Invest. 2007;117:3188-97. PMCID: PMC2045601
Full List of PubMed Publications
- 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. Sci Rep. 2016 Feb 18; 2016 Feb 18. PMID: 26888314
- Sakurai T, Lanahan A, Woolls MJ, Li N, Tirziu D, Murakami M: Live cell imaging of primary rat neonatal cardiomyocytes following adenoviral and lentiviral transduction using confocal spinning disk microscopy. J Vis Exp. 2014 Jun 24; 2014 Jun 24. PMID: 24998400
- Stacy MR, Yu DY, Maxfield MW, Jaba IM, Jozwik BP, Zhuang ZW, Lin BA, Hawley CL, Caracciolo CM, Pal P, Tirziu D, Sampath S, Sinusas AJ: Multimodality imaging approach for serial assessment of regional changes in lower extremity arteriogenesis and tissue perfusion in a porcine model of peripheral arterial disease. Circ Cardiovasc Imaging. 2014 Jan; 2013 Oct 29. PMID: 24170237
- 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. J Clin Invest. 2013 Apr. PMID: 23454748
- 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 Nov 27; 2012 Oct 22. PMID: 23091063
- Tirziu D, Giordano FJ, Simons M: Cell communications in the heart. Circulation. 2010 Aug 31. PMID: 20805439
- Tirziu D, Simons M: Endothelium as master regulator of organ development and growth. Vascul Pharmacol. 2009 Jan-Feb; 2008 Sep 5. PMID: 18804188
- Tirziu D, Simons M: Endothelium-driven myocardial growth or nitric oxide at the crossroads. Trends Cardiovasc Med. 2008 Nov. PMID: 19345317