Daniela Caliopia Tirziu PhD
Research Scientist in Medicine (Cardiology)
Endothelium-Cardiomyocyte Communication; Myocardial Hypertrophy; Angiogenesis; Nitric Oxide; Gi/Gq Signaling; microRNAs
- 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
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.
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.