Nicholas Leeper, Postdoctoral Faculty Sponsor
Role of cAMP in Cardiomyocyte Viability: Beneficial or Detrimental?
3', 5'-cyclic AMP (cAMP) regulates numerous cardiac functions. Various hormones and neurotransmitters elevate intracellular cAMP (i[cAMP]) in cardiomyocytes through activating stimulatory GsPCRs (G protein [Gs]-coupled receptors) and membrane-bound ACs (adenylyl cyclases). Increasing evidence has indicated that stimulating different GsPCRs and ACs exhibits distinct, even opposite effects, on cardiomyocyte viability. However, the underlying mechanisms are not fully understood.We used molecular and pharmacological approaches to investigate how different GsPCR/cAMP signaling differentially regulate cardiomyocyte viability with in vitro, ex vivo, and in vivo models.For prodeath GsPCRs, we explored beta1-adrenergic-receptor and histamine-H2-receptor. We found that their prodeath effects were similarly dependent on AC5 activation, ATP release to the extracellular space via PANX1 (pannexin-1) channel, and extracellular ATP (e[ATP])-mediated signaling involving in P2X7R (P2X purinoceptor 7) and CaMKII (Ca2+/calmodulin-dependent protein kinase II). PANX1 phosphorylation at Serine 206 by cAMP-dependent-PKA (protein-kinase-A) promoted PANX1 activation, which was critical in beta1-adrenergic-receptor- or histamine-H2-receptor-induced cardiomyocyte death in vitro and in vivo. Beta1-adrenergic-receptor or histamine-H2-receptor was localized proximately to PANX1, which permits ATP release. For prosurvival GsPCRs, we explored adenosine-A2-receptor (A2R), calcitonin-gene-related-peptide-receptor, and RXFP1 (relaxin-family peptide-receptor 1). Their prosurvival effects were dependent on AC6 activation, cAMP efflux via MRP4 (multidrug resistance protein 4), extracellular cAMP metabolism to adenosine (e[cAMP]-to-e[ADO]), and e[ADO]-mediated signaling. A2R, calcitonin-gene-related-peptide-receptor, or RXFP1 was localized proximately to MRP4, which enables cAMP efflux. Interestingly, exogenously increasing e[cAMP] levels by membrane-impermeable cAMP protected against cardiomyocyte death in vitro and in ex vivo and in vivo mouse hearts with ischemia-reperfusion injuries.Our findings indicate that the functional diversity of different GsPCRs in cardiomyocyte viability could be achieved by their ability to form unique signaling complexes (signalosomes) that determine the fate of cAMP: either stimulate ATP release by activating PKA or directly efflux to be e[cAMP].
View details for DOI 10.1161/CIRCRESAHA.123.322652
View details for PubMedID 37850368
Identifying shared transcriptional risk patterns between atherosclerosis and cancer.
2023; 26 (9): 107513
Cancer and cardiovascular disease (CVD) are the leading causes of death worldwide. Numerous overlapping pathophysiologic mechanisms have been hypothesized to drive the development of both diseases. Further investigation of these common pathways could allow for the identification of mutually detrimental processes and therapeutic targeting to derive mutual benefit. In this study, we intersect transcriptomic datasets correlated with disease severity or patient outcomes for both cancer and atherosclerotic CVD. These analyses confirmed numerous pathways known to underlie both diseases, such as inflammation and hypoxia, but also identified several novel shared pathways. We used these to explore common translational targets by applying the drug prediction software, OCTAD, to identify compounds that simultaneously reverse the gene expression signature for both diseases. These analyses suggest that certain tumor-specific therapeutic approaches may be implemented so that they avoid cardiovascular consequences, and in some cases may even be used to simultaneously target co-prevalent cancer and atherosclerosis.
View details for DOI 10.1016/j.isci.2023.107513
View details for PubMedID 37636064
View details for PubMedCentralID PMC10448075
- Spatial Metabolomics and the Vulnerable Atherosclerotic Plaque. Arteriosclerosis, thrombosis, and vascular biology 2023
Risk of Cancer After Diagnosis of Cardiovascular Disease.
2023; 5 (4): 431-440
Cardiovascular disease (CVD) and cancer share several risk factors. Although preclinical models show that various types of CVD can accelerate cancer progression, clinical studies have not determined the impact of atherosclerosis on cancer risk.The objective of this study was to determine whether CVD, especially atherosclerotic CVD, is independently associated with incident cancer.Using IBM MarketScan claims data from over 130 million individuals, 27 million cancer-free subjects with a minimum of 36 months of follow-up data were identified. Individuals were stratified by presence or absence of CVD, time-varying analysis with multivariable adjustment for cardiovascular risk factors was performed, and cumulative risk of cancer was calculated. Additional analyses were performed according to CVD type (atherosclerotic vs nonatherosclerotic) and cancer subtype.Among 27,195,088 individuals, those with CVD were 13% more likely to develop cancer than those without CVD (HR: 1.13; 95% CI: 1.12-1.13). Results were more pronounced for individuals with atherosclerotic CVD (aCVD), who had a higher risk of cancer than those without CVD (HR: 1.20; 95% CI: 1.19-1.21). aCVD also conferred a higher risk of cancer compared with those with nonatherosclerotic CVD (HR: 1.11; 95% CI: 1.11-1.12). Cancer subtype analyses showed specific associations of aCVD with several malignancies, including lung, bladder, liver, colon, and other hematologic cancers.Individuals with CVD have an increased risk of developing cancer compared with those without CVD. This association may be driven in part by the relationship of atherosclerosis with specific cancer subtypes, which persists after controlling for conventional risk factors.
View details for DOI 10.1016/j.jaccao.2023.01.010
View details for PubMedID 37614573
View details for PubMedCentralID PMC10443115
- Clustering cancers by shared transcriptional risk reveals novel targets for cancer therapy. Molecular cancer 2022; 21 (1): 116
The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis.
Nature cardiovascular research
2022; 1 (3): 253-262
The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. Here, RNA sequencing designed to investigate gene expression patterns following CD47-SIRPalpha inhibition identifies a link between statins, efferocytosis, and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NFkappaB1 p50 and suppressing the expression of the critical 'don't eat me' molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47-SIRPalpha blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of pro-phagocytic therapies independently of any lipid-lowering effect.
View details for DOI 10.1038/s44161-022-00023-x
View details for PubMedID 35990913
Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells.
AIMS: De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'.METHODS AND RESULTS: Genome-wide sequencing studies, including ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) and RNA-seq, were performed on cells isolated from both murine SMC-lineage tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, ATF3 (Activating transcription factor 3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 were negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly downregulated in humans with advanced vascular disease.CONCLUSION: Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress.TRANSLATIONAL PERSPECTIVE: The recent CANTOS and COLCOT trials have shown that targeting inflammatory pathways lowers the risk of major adverse cardiovascular events. However, more specific targets are needed to avoid immunosuppressive side effects. Our data identify an upstream regulator of pro-inflammatory SMCs, ATF3, which is involved in the initial atherogenic transitioning of lesional SMCs. Restoring ATF3 activity may prevent the de-differentiation of SMCs and offer a novel translational approach for the suppression of complement-dependent inflammation in atherosclerotic lesions.
View details for DOI 10.1093/cvr/cvab347
View details for PubMedID 34849613
Efficient suppression of vascular smooth muscle cell proliferation and intimal hyperplasia by targeting phosphodiesterase 10A
SAGE PUBLICATIONS LTD. 2021: NP4-NP5
View details for Web of Science ID 000704017100022
Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodeling
View details for DOI 10.1093/cvr/cvab304