Background: During the future Moon and Mars missions, astronauts will be exposed to space radiati... more Background: During the future Moon and Mars missions, astronauts will be exposed to space radiation (IR) for extended time. The majority of space flight-associated risks identified for the cardiovascular (CV) system to date were determined shortly after low Earth orbit (LEO) short- and long-duration space flights that include: serious cardiac dysrhythmias, compromised orthostatic CV response and manifestation of previously asymptomatic CV disease. Further ground-based experiments using a surrogate model of microgravity supported the space flight data for significant cardiac remodeling due to prolonged exposure to microgravity. These symptoms were determined to be a consequence of adaptation to microgravity that could be ameliorated by a post-mission exercise program, and were not identified as risk factors that were causatively related to space IR. Long-term degenerative effects of cosmic IR during and after space flights on CV system are unknown. It was suggested that due to GCR, each cell in an astronaut’s body will be traversed by 1 H every 3 days, helium ( 2 He) nuclei every few weeks and high charge and energy (HZE) nuclei (e.g. 28 Si, 56 Fe) every few months. Despite the fact that only 1% of GCR is composed of ions heavier than helium, ~41% of the IR dose-equivalent is predicted to be HZE particles with 13% being from 56 Fe particles, only. During an exploration-class space mission to Mars, astronauts will not have access to comprehensive healthcare services for a period of at least 2–3 years. Since the majority of experienced astronauts are middle-aged (average age is 46, and the range is 33–58 years), they are at risk for developing serious CV events which could be lifethreatening for the astronaut and mission-threatening for NASA. Therefore, it is important to evaluate the effects and potential CV risks caused by space IR. We hypothesized that: (i) low-dose space IR-induced biological responses may be long-lasting and are IR type-dependent; (ii) IR may increase CV risks in the aging heart (IR + AGING model) and affect the heart recovery after an adverse CV event, such as acute myocardial infarct (IR + AGING + AMI model). Methods: Eight- to 9-month-old C57BL/6N male mice were IR once with proton ( 1 H) 50 cGy, 1 GeV/n or iron ( 56 Fe) 15 cGy, 1 GeV/n. We evaluated IR-induced biological tissue responses—underlying molecular mechanisms, calcium handling, signal transduction, gene expression and cardiac fibrosis. Cardiac function was assessed by echocardiography (ECHO) and hemodynamic measurements (HEMO) as detailed in Fig. 1. AMI was induced by ligation of left anterior descending coronary artery 1 and 3 months post-IR as detailed in Fig. 2. Results: In the IR + AGING model, cardiac function was not different among the control and 1 H-IR group, whereas left ventricular end-diastolic pressure (LVEDP) was significantly increased in 56 Fe mice 1 and 3 months post-IR. There was a small but statistically significant (P 200% increases, P< 0.02) and 400% decreases in p-p38 MAPK (P < 0.05), suggesting activation of compensatory mechanisms in [Ca 2+ ]i handling in these hearts. By 3 months, compared with control, 1 H- and 56 Fe-IR hearts had 200–500% (P< 0.02) decreases in SERCA2a and more than 200% decreases in p-Creb-1 (P< 0.02), suggesting reduced capacity in intracellular
TNF-α (TNF) binds two receptors TNFR1-p55 and TNFR2-p75. Ionizing radiation (IR) increases tissue... more TNF-α (TNF) binds two receptors TNFR1-p55 and TNFR2-p75. Ionizing radiation (IR) increases tissue TNF levels. TNF signaling regulates numerous cyto- and chemokines, known to mediate radiation-induced non-targeted effects (NTE), a phenomenon where cells that are not directly “hit” by IR exhibit IR effects as a result of signals received from nearby or distant IR cells. Little is known about the role of p55 or p75 in regulating NTEs in bone marrow (BM)-derived EPCs. We hypothesized that inhibition of TNF signaling either via p55, or p75 may alter TNF-mediated inflammatory responses, inducing NTEs. Medium transfer experiments (MTE) were performed in WT, p55 knockout(KO) and p75KO BM-derived EPC ex-vivo, where one set of EPCs was irradiated with 1Gy of γ-IR, then IR-conditioned medium (CM) was collected from these dishes at 1, 5, 24h and 3, 5d post-IR. Filtered (0.22µm) IR-CM was transferred to naïve non-IR same genotype EPCs and 24h post-incubation naïve EPCs were processed for p-y-H2AX staining for presence and decay of double strand breaks (DSB). CM from IR EPCs were processed for ELISA profiling (16 genes) and IR EPCs were processed for transcriptional profiling. In WT EPC the peak of detectable mean p-y-H2AX foci/cell were at 24h, whereas in p55 and p75KOs p-y-H2AX were the lowest at 24h (9±0.8 vs 4.8±0.6 and 3.7±0.5, p&amp;amp;lt;0.01 and 0.001, WT vs p55 and p75KOs). This finding indicates that altered TNF signaling inhibits early NTEs (hours) in EPCs. Compared to WT, delayed (5 days) NTEs were amplified in naïve p55 and p75KO EPCs (3.8±0.4 vs 8.5±1 and 5.9±0.8, p&amp;amp;lt;0.02 and 0.01, WT vs p55 and p75KOs), suggesting significant role for TNF signaling in mediating delayed NTEs. ELISA profiling of 16 proteins in CM over 5 days post-IR showed 200-1600% increases (p&amp;amp;lt;0.002, p55KO vs WT) in cumulative levels of TNF, IFNr, IL6, EGF, MIP-1α, GM-SCF, Rantes, and 200-1000%, increases (p&amp;amp;lt;0.05, p75KO vs WT) in IL1α, IL1β, G -CSF, MCP-1, SCF. Transcriptional profiling of γ-IR EPC revealed 139 genes (&amp;amp;gt;2 fold) up or down regulated, clustered into 9 groups. Other aspects of gene array data are being considered. We conclude that TNF ligand-receptor axis regulates NTEs in naïve EPCs and suggest that restoring TNF signaling balance could be used to prevent delayed NTEs in distant from primary IR target tissues.
Background: Endothelial to mesenchymal transition (EndMT), play critical role in pressure overloa... more Background: Endothelial to mesenchymal transition (EndMT), play critical role in pressure overload-induced pathological fibrosis. Recent studies suggested the contribution of fibroblasts-derived ex...
Aging is a risk factor for ischemic diseases. TNF-α, a pro-inflammatory cytokine, is expressed in... more Aging is a risk factor for ischemic diseases. TNF-α, a pro-inflammatory cytokine, is expressed in ischemic tissues and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling and muscle regeneration. We studied neovascularization in the hind limb ischemia (HLI) model in young and old TNFR2/p75 knockout (p75KO) and wild type (WT) age-matched controls. Between days 7–10 post-HL surgery 100% of old p75KOs experienced auto-amputation of the operated limbs, whereas none of the age-matched WT mice exhibited HL necrosis. Poor blood flow recovery in p75KOs was associated with decreased capillary density and significant reduction in the expression of VEGF mRNA transcripts in ischemic tissue. Compared to presurgery, on days 1–10 post-HL surgery there was 6–10-fold increase in the number of satellite-cells (embrionic NCAM staining) in WT mice, whereas in p75KOs after day 1 through day 10 satellite cells were not detecable. Indeed, p75KO tissue showed increased and prolonged (via day 10) inflammation - neutrophil (MPO-1) and macrophage (F/480) infiltration. Transplantation of WT/GFP (+) BM mononuclear cells into γ-irradiated p75KOs one month prior to HL surgery prevented limb loss, suggesting that ischemia-induced neovascularization and mobilization of BM-derived cells is mediated, at least in part, via TNFR2/p75 expressed in BM-derived cells. In the same BM transplantation model we evaluated the rate of proliferation (Ki67 + cells) of resident GFP (−) vs BM-derived GFP (+) cells. We found that in both WT and p75KO ischemic tissue Ki67 (+) cells almost exclusively were GFP (+), indicating that only BM-derived cells proliferate in the ischemic tissue. Interestingly, Ki67/GFP (+) cells started to appear in WT tissue by day 3 through day 21, whereas in p75KO tissue first proliferative activity was detected on day 28, suggesting extremely delayed recovery and regenaration in p75KO tissue. Our study suggests that, signaling through p75 receptor is required for collateral vessel development in ischemia-induced neovascularization as well as plays a critical role in muscle regeneration and suggest a potential gene target, which could be used to improve the repair of ischemic tissue in adults.
Poor differentiation ability might be the barrier for the stem cell based therapy in ischemic myo... more Poor differentiation ability might be the barrier for the stem cell based therapy in ischemic myocardium. Epigenetic regulation play a critical role in this cell fate commitment, however, the mecha...
Background: Recent studies have demonstrated that exosomes from diabetic animals/cells have detri... more Background: Recent studies have demonstrated that exosomes from diabetic animals/cells have detrimental effects on the post-injury vascular repair. Here, we tested the hypothesis that systemic exosome inhibition in vivo improves blood flow recovery in ischemic hindlimbs of diabetic db/db following surgical ischemia. Methods and Results: Exosomes were isolated from plasma of non-diabetic db/+ and diabetic db/db mice by standard ultracentrifugation method. Unilateral hindlimb ischemia surgery was conducted by ligation of left femoral artery in 12-week old, male db/+ and db/db mice. Exosome inhibitor GW-4869 (GW, 2 μg/g body weight) was administrated by intraperitoneal injection every other day for 4 weeks starting from one week before the hindlimb ischemia (HLI) surgery. HLI mice injected with vehicle served as controls. Mice were divided into four groups: 1) db/+ + vehicle; 2) db/db+ vehicle; 3) db/+ GW; 4) db/db + GW. We found that systemic administration of GW decreased necrosis and loss of toe/toenail, ...
Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their... more Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their origin in diseased heart remains uncertain. Previous studies suggest the contribution of bone marrow fibroblasts progenitor cells (FPC) in pressure overload (PO)-induced cardiac fibrosis and inflammation acts as catalyst in this process. Recently others and we have shown that paracrine mediators packaged in exosomes play important role in cardiac pathophysiology. Thus, we hypothesized that exosome-derived from IL10KO-FPC augments PO-induced resident cardiac fibroblast activation and therefore, aggravate cardiac fibrosis. Methods and Results: Cardiac fibrosis was induced in Wild-type (WT) and IL10-knockout (IL10KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in IL10KO mice. PO-enhanced FPC (Prominin1 + cells) mobilization and homing in IL10KO mice compared to WT mice. To establish the IL10KO-FPC paracrine signaling, exosomes were isolated from WT and IL10KO BM-FPC culture media and characterized for proteins/miRNA. IL10 KO FPC-exosomes showed altered packaging of signature fibrotic miR and proteins. To explore whether FPC-exosomes modulate resident fibroblast activation, adult cardiac fibroblasts were treated with WT and IL10KO FPC-derived exosomes. IL10KO-FPC-derived exosomes exaggerate TGFβ 2 -induced activation of adult fibroblasts. These data suggest that fibrotic remodeling factors (miRs and/or proteins) packaged in IL10KO-FPC exosomes are sufficient to enhance the resident cardiac fibroblast activation and mediate cardiac fibrotic remodeling IL10 treatment significantly inhibits TGFβ 2 -induced FPC to myoFBs transition. Conclusion: Taken together, our findings suggest that paracrine factors secreted by BM-FPC augment resident cardiac fibroblast activation and fibrosis in pressure overloaded myocardium and IL10 negatively regulates this process. Ongoing investigations using molecular approaches will provide a better understanding on the mechanistic and therapeutic aspects of IL10 on PO-induced cardiac fibrosis and heart failure.
Recent studies highlighted that circular RNAs (circRNA) can play an important role in cardiac hyp... more Recent studies highlighted that circular RNAs (circRNA) can play an important role in cardiac hypertrophy. However, the circRNAs in cardiac diseases is still limited. Using global circRNA expression profiling, we identified several circRNA transcripts that were differentially regulated post-MI in mice, including mmu_circ_008396 that is significantly down regulated. Cell fractionation experiments indicated that mmu_circ_008396 is highly enriched in endothelial cells in post-MI mice. Interestingly, we found a mmu_circ_008396 circRNA ortholog in humans, which was also significantly down regulated in ischemic cardiomyopathy patients. Further, overexpression of mmu_circ_008396 significantly enhanced tube formation and reduced apoptosis of human umbilical vein endothelial cells. For cardiac overexpression of mmu_circ_008396 circRNA, we created AAV9 viral particles and found that in vivo over expression attenuated LV dysfunction post-MI and enhanced neovascularization. Mechanistically, mmu_circ_008396 binds to its potential target miRNAs (mmu-miR-93-3p, mmu-miR-412-3p and mmu-miR-298-5p) and regulate hemeoxygenase-1/ VEGF signaling, thereby enhancing neovascularization and cardiac repair post-MI. These results indicate that mmu_circ_008396 circRNA might be a novel potential target to prevent cardiac remodeling and also highlight the significance of circRNAs in cardiovascular diseases.
Introduction: Circular RNAs (CircRNAs) are a new addition to the list of growing body of non-codi... more Introduction: Circular RNAs (CircRNAs) are a new addition to the list of growing body of non-coding RNAs. Recent studies highlighted that CircRNA can play an important role in cardiac hypertrophy. ...
Background: During the future Moon and Mars missions, astronauts will be exposed to space radiati... more Background: During the future Moon and Mars missions, astronauts will be exposed to space radiation (IR) for extended time. The majority of space flight-associated risks identified for the cardiovascular (CV) system to date were determined shortly after low Earth orbit (LEO) short- and long-duration space flights that include: serious cardiac dysrhythmias, compromised orthostatic CV response and manifestation of previously asymptomatic CV disease. Further ground-based experiments using a surrogate model of microgravity supported the space flight data for significant cardiac remodeling due to prolonged exposure to microgravity. These symptoms were determined to be a consequence of adaptation to microgravity that could be ameliorated by a post-mission exercise program, and were not identified as risk factors that were causatively related to space IR. Long-term degenerative effects of cosmic IR during and after space flights on CV system are unknown. It was suggested that due to GCR, each cell in an astronaut’s body will be traversed by 1 H every 3 days, helium ( 2 He) nuclei every few weeks and high charge and energy (HZE) nuclei (e.g. 28 Si, 56 Fe) every few months. Despite the fact that only 1% of GCR is composed of ions heavier than helium, ~41% of the IR dose-equivalent is predicted to be HZE particles with 13% being from 56 Fe particles, only. During an exploration-class space mission to Mars, astronauts will not have access to comprehensive healthcare services for a period of at least 2–3 years. Since the majority of experienced astronauts are middle-aged (average age is 46, and the range is 33–58 years), they are at risk for developing serious CV events which could be lifethreatening for the astronaut and mission-threatening for NASA. Therefore, it is important to evaluate the effects and potential CV risks caused by space IR. We hypothesized that: (i) low-dose space IR-induced biological responses may be long-lasting and are IR type-dependent; (ii) IR may increase CV risks in the aging heart (IR + AGING model) and affect the heart recovery after an adverse CV event, such as acute myocardial infarct (IR + AGING + AMI model). Methods: Eight- to 9-month-old C57BL/6N male mice were IR once with proton ( 1 H) 50 cGy, 1 GeV/n or iron ( 56 Fe) 15 cGy, 1 GeV/n. We evaluated IR-induced biological tissue responses—underlying molecular mechanisms, calcium handling, signal transduction, gene expression and cardiac fibrosis. Cardiac function was assessed by echocardiography (ECHO) and hemodynamic measurements (HEMO) as detailed in Fig. 1. AMI was induced by ligation of left anterior descending coronary artery 1 and 3 months post-IR as detailed in Fig. 2. Results: In the IR + AGING model, cardiac function was not different among the control and 1 H-IR group, whereas left ventricular end-diastolic pressure (LVEDP) was significantly increased in 56 Fe mice 1 and 3 months post-IR. There was a small but statistically significant (P 200% increases, P< 0.02) and 400% decreases in p-p38 MAPK (P < 0.05), suggesting activation of compensatory mechanisms in [Ca 2+ ]i handling in these hearts. By 3 months, compared with control, 1 H- and 56 Fe-IR hearts had 200–500% (P< 0.02) decreases in SERCA2a and more than 200% decreases in p-Creb-1 (P< 0.02), suggesting reduced capacity in intracellular
TNF-α (TNF) binds two receptors TNFR1-p55 and TNFR2-p75. Ionizing radiation (IR) increases tissue... more TNF-α (TNF) binds two receptors TNFR1-p55 and TNFR2-p75. Ionizing radiation (IR) increases tissue TNF levels. TNF signaling regulates numerous cyto- and chemokines, known to mediate radiation-induced non-targeted effects (NTE), a phenomenon where cells that are not directly “hit” by IR exhibit IR effects as a result of signals received from nearby or distant IR cells. Little is known about the role of p55 or p75 in regulating NTEs in bone marrow (BM)-derived EPCs. We hypothesized that inhibition of TNF signaling either via p55, or p75 may alter TNF-mediated inflammatory responses, inducing NTEs. Medium transfer experiments (MTE) were performed in WT, p55 knockout(KO) and p75KO BM-derived EPC ex-vivo, where one set of EPCs was irradiated with 1Gy of γ-IR, then IR-conditioned medium (CM) was collected from these dishes at 1, 5, 24h and 3, 5d post-IR. Filtered (0.22µm) IR-CM was transferred to naïve non-IR same genotype EPCs and 24h post-incubation naïve EPCs were processed for p-y-H2AX staining for presence and decay of double strand breaks (DSB). CM from IR EPCs were processed for ELISA profiling (16 genes) and IR EPCs were processed for transcriptional profiling. In WT EPC the peak of detectable mean p-y-H2AX foci/cell were at 24h, whereas in p55 and p75KOs p-y-H2AX were the lowest at 24h (9±0.8 vs 4.8±0.6 and 3.7±0.5, p&amp;amp;lt;0.01 and 0.001, WT vs p55 and p75KOs). This finding indicates that altered TNF signaling inhibits early NTEs (hours) in EPCs. Compared to WT, delayed (5 days) NTEs were amplified in naïve p55 and p75KO EPCs (3.8±0.4 vs 8.5±1 and 5.9±0.8, p&amp;amp;lt;0.02 and 0.01, WT vs p55 and p75KOs), suggesting significant role for TNF signaling in mediating delayed NTEs. ELISA profiling of 16 proteins in CM over 5 days post-IR showed 200-1600% increases (p&amp;amp;lt;0.002, p55KO vs WT) in cumulative levels of TNF, IFNr, IL6, EGF, MIP-1α, GM-SCF, Rantes, and 200-1000%, increases (p&amp;amp;lt;0.05, p75KO vs WT) in IL1α, IL1β, G -CSF, MCP-1, SCF. Transcriptional profiling of γ-IR EPC revealed 139 genes (&amp;amp;gt;2 fold) up or down regulated, clustered into 9 groups. Other aspects of gene array data are being considered. We conclude that TNF ligand-receptor axis regulates NTEs in naïve EPCs and suggest that restoring TNF signaling balance could be used to prevent delayed NTEs in distant from primary IR target tissues.
Background: Endothelial to mesenchymal transition (EndMT), play critical role in pressure overloa... more Background: Endothelial to mesenchymal transition (EndMT), play critical role in pressure overload-induced pathological fibrosis. Recent studies suggested the contribution of fibroblasts-derived ex...
Aging is a risk factor for ischemic diseases. TNF-α, a pro-inflammatory cytokine, is expressed in... more Aging is a risk factor for ischemic diseases. TNF-α, a pro-inflammatory cytokine, is expressed in ischemic tissues and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling and muscle regeneration. We studied neovascularization in the hind limb ischemia (HLI) model in young and old TNFR2/p75 knockout (p75KO) and wild type (WT) age-matched controls. Between days 7–10 post-HL surgery 100% of old p75KOs experienced auto-amputation of the operated limbs, whereas none of the age-matched WT mice exhibited HL necrosis. Poor blood flow recovery in p75KOs was associated with decreased capillary density and significant reduction in the expression of VEGF mRNA transcripts in ischemic tissue. Compared to presurgery, on days 1–10 post-HL surgery there was 6–10-fold increase in the number of satellite-cells (embrionic NCAM staining) in WT mice, whereas in p75KOs after day 1 through day 10 satellite cells were not detecable. Indeed, p75KO tissue showed increased and prolonged (via day 10) inflammation - neutrophil (MPO-1) and macrophage (F/480) infiltration. Transplantation of WT/GFP (+) BM mononuclear cells into γ-irradiated p75KOs one month prior to HL surgery prevented limb loss, suggesting that ischemia-induced neovascularization and mobilization of BM-derived cells is mediated, at least in part, via TNFR2/p75 expressed in BM-derived cells. In the same BM transplantation model we evaluated the rate of proliferation (Ki67 + cells) of resident GFP (−) vs BM-derived GFP (+) cells. We found that in both WT and p75KO ischemic tissue Ki67 (+) cells almost exclusively were GFP (+), indicating that only BM-derived cells proliferate in the ischemic tissue. Interestingly, Ki67/GFP (+) cells started to appear in WT tissue by day 3 through day 21, whereas in p75KO tissue first proliferative activity was detected on day 28, suggesting extremely delayed recovery and regenaration in p75KO tissue. Our study suggests that, signaling through p75 receptor is required for collateral vessel development in ischemia-induced neovascularization as well as plays a critical role in muscle regeneration and suggest a potential gene target, which could be used to improve the repair of ischemic tissue in adults.
Poor differentiation ability might be the barrier for the stem cell based therapy in ischemic myo... more Poor differentiation ability might be the barrier for the stem cell based therapy in ischemic myocardium. Epigenetic regulation play a critical role in this cell fate commitment, however, the mecha...
Background: Recent studies have demonstrated that exosomes from diabetic animals/cells have detri... more Background: Recent studies have demonstrated that exosomes from diabetic animals/cells have detrimental effects on the post-injury vascular repair. Here, we tested the hypothesis that systemic exosome inhibition in vivo improves blood flow recovery in ischemic hindlimbs of diabetic db/db following surgical ischemia. Methods and Results: Exosomes were isolated from plasma of non-diabetic db/+ and diabetic db/db mice by standard ultracentrifugation method. Unilateral hindlimb ischemia surgery was conducted by ligation of left femoral artery in 12-week old, male db/+ and db/db mice. Exosome inhibitor GW-4869 (GW, 2 μg/g body weight) was administrated by intraperitoneal injection every other day for 4 weeks starting from one week before the hindlimb ischemia (HLI) surgery. HLI mice injected with vehicle served as controls. Mice were divided into four groups: 1) db/+ + vehicle; 2) db/db+ vehicle; 3) db/+ GW; 4) db/db + GW. We found that systemic administration of GW decreased necrosis and loss of toe/toenail, ...
Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their... more Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their origin in diseased heart remains uncertain. Previous studies suggest the contribution of bone marrow fibroblasts progenitor cells (FPC) in pressure overload (PO)-induced cardiac fibrosis and inflammation acts as catalyst in this process. Recently others and we have shown that paracrine mediators packaged in exosomes play important role in cardiac pathophysiology. Thus, we hypothesized that exosome-derived from IL10KO-FPC augments PO-induced resident cardiac fibroblast activation and therefore, aggravate cardiac fibrosis. Methods and Results: Cardiac fibrosis was induced in Wild-type (WT) and IL10-knockout (IL10KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in IL10KO mice. PO-enhanced FPC (Prominin1 + cells) mobilization and homing in IL10KO mice compared to WT mice. To establish the IL10KO-FPC paracrine signaling, exosomes were isolated from WT and IL10KO BM-FPC culture media and characterized for proteins/miRNA. IL10 KO FPC-exosomes showed altered packaging of signature fibrotic miR and proteins. To explore whether FPC-exosomes modulate resident fibroblast activation, adult cardiac fibroblasts were treated with WT and IL10KO FPC-derived exosomes. IL10KO-FPC-derived exosomes exaggerate TGFβ 2 -induced activation of adult fibroblasts. These data suggest that fibrotic remodeling factors (miRs and/or proteins) packaged in IL10KO-FPC exosomes are sufficient to enhance the resident cardiac fibroblast activation and mediate cardiac fibrotic remodeling IL10 treatment significantly inhibits TGFβ 2 -induced FPC to myoFBs transition. Conclusion: Taken together, our findings suggest that paracrine factors secreted by BM-FPC augment resident cardiac fibroblast activation and fibrosis in pressure overloaded myocardium and IL10 negatively regulates this process. Ongoing investigations using molecular approaches will provide a better understanding on the mechanistic and therapeutic aspects of IL10 on PO-induced cardiac fibrosis and heart failure.
Recent studies highlighted that circular RNAs (circRNA) can play an important role in cardiac hyp... more Recent studies highlighted that circular RNAs (circRNA) can play an important role in cardiac hypertrophy. However, the circRNAs in cardiac diseases is still limited. Using global circRNA expression profiling, we identified several circRNA transcripts that were differentially regulated post-MI in mice, including mmu_circ_008396 that is significantly down regulated. Cell fractionation experiments indicated that mmu_circ_008396 is highly enriched in endothelial cells in post-MI mice. Interestingly, we found a mmu_circ_008396 circRNA ortholog in humans, which was also significantly down regulated in ischemic cardiomyopathy patients. Further, overexpression of mmu_circ_008396 significantly enhanced tube formation and reduced apoptosis of human umbilical vein endothelial cells. For cardiac overexpression of mmu_circ_008396 circRNA, we created AAV9 viral particles and found that in vivo over expression attenuated LV dysfunction post-MI and enhanced neovascularization. Mechanistically, mmu_circ_008396 binds to its potential target miRNAs (mmu-miR-93-3p, mmu-miR-412-3p and mmu-miR-298-5p) and regulate hemeoxygenase-1/ VEGF signaling, thereby enhancing neovascularization and cardiac repair post-MI. These results indicate that mmu_circ_008396 circRNA might be a novel potential target to prevent cardiac remodeling and also highlight the significance of circRNAs in cardiovascular diseases.
Introduction: Circular RNAs (CircRNAs) are a new addition to the list of growing body of non-codi... more Introduction: Circular RNAs (CircRNAs) are a new addition to the list of growing body of non-coding RNAs. Recent studies highlighted that CircRNA can play an important role in cardiac hypertrophy. ...
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