Although heart failure is inevitable disease, its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure, the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately, during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress, leading to failure. Remodeling by its very nature implies synthesis, degradation, and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer, architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1, a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released, The hypothesis will be tested by following three specific aims:
Specific Aim #1 : To determine whether the induction of MMP-2, PAR-1, G1s, and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure.
Specific Aim #2 : To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure.
Specific Aim #3 : To determine whether the mitochondrial mitophagy attenuates angiogenesis, in part, by activating MMP-9, releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1, MMP, TIMP, G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.
These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.
|Veeranki, Sudhakar; Tyagi, Suresh C (2017) Dysbiosis and Disease: Many Unknown Ends, Is It Time to Formulate Guidelines for Dysbiosis Research? J Cell Physiol 232:2929-2930|
|Veeranki, Sudhakar; Gandhapudi, Siva K; Tyagi, Suresh C (2017) Interactions of hyperhomocysteinemia and T cell immunity in causation of hypertension. Can J Physiol Pharmacol 95:239-246|
|Veeranki, Sudhakar; Givvimani, Srikanth; Kundu, Sourav et al. (2016) Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice. J Mol Cell Cardiol 92:163-173|
|Muradashvili, Nino; Tyagi, Reeta; Tyagi, Neetu et al. (2016) Cerebrovascular disorders caused by hyperfibrinogenaemia. J Physiol 594:5941-5957|
|Chaturvedi, Pankaj; Kamat, Pradip K; Kalani, Anuradha et al. (2016) High Methionine Diet Poses Cardiac Threat: A Molecular Insight. J Cell Physiol 231:1554-61|
|Chernyavskiy, Ilya; Veeranki, Sudhakar; Sen, Utpal et al. (2016) Atherogenesis: hyperhomocysteinemia interactions with LDL, macrophage function, paraoxonase 1, and exercise. Ann N Y Acad Sci 1363:138-54|
|Amin, Matthew; Pushpakumar, Sathnur; Muradashvili, Nino et al. (2016) Regulation and involvement of matrix metalloproteinases in vascular diseases. Front Biosci (Landmark Ed) 21:89-118|
|Kunkel, George H; Chaturvedi, Pankaj; Tyagi, Suresh C (2016) Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail Rev 21:499-517|
|Givvimani, Srikanth; Kundu, Sourav; Pushpakumar, Sathnur et al. (2015) Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1. Can J Physiol Pharmacol 93:755-63|
|Chaturvedi, Pankaj; Kalani, Anuradha; Medina, Ilza et al. (2015) Cardiosome mediated regulation of MMP9 in diabetic heart: role of mir29b and mir455 in exercise. J Cell Mol Med 19:2153-61|
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