Elucidating the Genetic Basis of Peripheral Arterial Disease

Messina, Louis M.

doi:10.1161/circulationaha.107.752055

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…Variations in the clinical course of CLI raise the intriguing possibility that disease manifestation is in part dependent on genetic determinants of susceptibility to ischemia (Matzke and Lepantalo, 2001 ; Chalothorn et al, 2007 ; Dokun et al, 2008 ; Chalothorn and Faber, 2010 ; Wang et al, 2010 , 2012 ; Katwal and Dokun, 2011 ). The genetics of PAD are not well understood (Gudmundsson et al, 2002 ; Knowles et al, 2007 ; Messina, 2008 ; Katwal and Dokun, 2011 ; Leeper et al, 2012 ; Murabito et al, 2012 ) but present a complicated paradigm whereby differential determinants could direct the ischemic responses of multiple cell types (endothelial, muscle, fibroblast, etc.) in the affected limb.…”

Section: Skeletal Muscle Pathology In the Ischemic Limbmentioning

confidence: 99%

Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia

et al. 2015

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Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI.

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Section: Skeletal Muscle Pathology In the Ischemic Limbmentioning

confidence: 99%

Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia

et al. 2015

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“…Although progress has been made in elucidating the contribution of genetic factors to the development of peripheral artery disease (PAD) 1–6 , no alleles that modulate patients’ susceptibility to critical limb ischemia (CLI) are presently known. Historically, it was felt that CLI represented the natural progression of PAD in patients with intermittent claudication.…”

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confidence: 99%

BAG3 (Bcl-2–Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy

et al. 2017

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Background Critical limb ischemia (CLI) is a manifestation of peripheral artery disease (PAD) that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered two overlapping quantitative trait loci (QTL) in mice, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume following femoral artery or middle cerebral artery ligation, respectively. Here we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hindlimb ischemia (HLI). Methods We treated mice with either adeno-associated viruses (AAV) encoding a control (GFP), or two BAG3 variants, namely Met81 or Ile81, and subjected the mice to hindlimb ischemia. Results We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6-Lsq1-3). Treating BALB/c mice with AAV encoding the BL6 BAG3 variant (Ile81) (n=25) displayed reduced limb tissue necrosis and increased limb tissue perfusion compared to Met81- (n=25) or GFP- (n=29) expressing animals. BAG3Ile81, but not BAG3Met81, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of AAV-BAG3Ile81 (n=9), but not BAG3Met81 (n=10) or GFP (n=5), improved ischemic limb blood flow, limb muscle histology, and restored muscle function (force production). Compared to BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Conclusions Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.

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Elucidating the Genetic Basis of Peripheral Arterial Disease

Cited by 2 publications

References 19 publications

Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia

Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia

BAG3 (Bcl-2–Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy

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